MYRF mutation leads to a single manifestation of sexual development and mimics partial androgen insensitivity syndrome: a case report and literature review.

OBJECTIVE: To highlight the challenges in diagnosing 46, XY disorder of sex development related to MYRF mutation. METHODS: We present an unusual case of a 12-year-old female child came for enlargement of clitoris and initially diagnosed as partial androgen insensitivity syndrome (AIS). RESULTS: On examination, the patient's vulva was found virilized with 3cm-long clitoris. Her peripheral blood karyotype was 46, XY. The ultrasound showed an empty pelvis and hormone results confirmed hyperandrogenism. Therefore, the partial AIS was suspected, but the following whole exon sequencing indicates a pathological missense mutation in MYRF. Further investigation and surgery did not reveal any brain, heart, lung or diaphragm lesions related to MYRF, but only maldeveloped internal genitalia and a persistent urachus. Her serum testosterone dropped to normal after surgical removal of the remaining ipsilateral testis and epididymitis without spermatogenesis as shown by pathology. CONCLUSION: Due to the karyotype, hyperandrogenism, empty pelvis but a virilism after puberty, the patient was initially diagnosed as partial AIS. This misleading clinical diagnose will not be verified as the MYRF mutation if without the whole exon sequencing, particularly in the absence of obvious brain, heart, lung and diaphragm lesions as in this case.

Unmet needs in abnormal uterine bleeding due to ovulatory dysfunction.

Ovulatory disorders are a common cause of abnormal uterine bleeding in women of reproductive age. The International Federation of Gynecology and Obstetrics currently offers a causal classification system for ovulatory disorders but does not provide clear management recommendations. There remains regional disparity in treatment practices, often influenced by institutional and insurance regulations as well as cultural and religious practices. A panel of experts evaluated current gaps in ovulatory disorder management guidelines and discussed potential strategies for addressing these unmet needs. Key gaps included a lack in consensus about the effectiveness of combined estrogen and progestogen versus progestogen alone, a paucity of evidence regarding the relative effectiveness of distinct hormonal molecules, a lack of data regarding optimal treatment duration, and limited guidance on optimal sequencing of treatment. Recommendations included development of a sequential treatment-line approach and development of a clinical guide addressing treatment scenarios common to all countries, which can then be adapted to local practices. It was also agreed that current guidelines do not address the unique clinical challenges of certain patient groups. The panel discussed how the complexity and variety of patient groups made the development of one single disease management algorithm unlikely; however, a simplified, decision-point hierarchy could potentially help direct therapeutic choices. Overall, the panel highlighted that greater advocacy for a tailored approach to the treatment of ovulatory disorders, including wider consideration of non-estrogen therapies, could help to improve care for people living with abnormal uterine bleeding due to ovarian dysfunction.

Clinical characteristics and management of Turner patients with a small supernumerary marker chromosome.

OBJECTIVE: To summarize the clinical characteristics of Turner syndrome (TS) with a small supernumerary marker chromosome (sSMC) and discuss the clinical significance and management of TS patients with sSMC. METHODS: A retrospective analysis was conducted on the clinical data of 244 patients with disorders of sexual development admitted to Peking Union Medical College Hospital from February 1984 to July 2020. RESULTS: Among the 244 patients with a disorder of sexual development, 69 cases of TS were identified in which 13 patients had sSMC. Their ages ranged from 3 to 28 years old with an average of 14.31 ± 6.40 years. All 13 sSMC-positive patients had typical clinical manifestations of TS except ambiguous genitalia in four cases. SRY gene testing was performed in 11sSMC-positive patients and 10 patients were positive for SRY and one was negative. Among the 10 SRY-positive patients, two cases had hirsutism and clitoral enlargement and two cases had clitoral enlargement only. Nine sSMC and SRY-positive patients underwent gonadectomy and one had left gonadal gonadoblastoma with seminoma in situ and right gonadal seminoma in situ. CONCLUSIONS: Although the sSMC positive detection rate in DSD patients is uncommon (5.33% in our sample), the positive SRY detection rate in sSMC-positive TS patients was extremely high in our TS patients. And TS patients with sSMC and SRY positive had a significantly increased risk of gonadal germ cell tumors. Routine SRY screening should be performed in TS patients with sSMC, and a gonadectomy should be performed in TS patients with sSMC and SRY positive to prevent the occurrence of tumors.

Heavy menstrual bleeding among women aged 18-50 years living in Beijing, China: prevalence, risk factors, and impact on daily life.

BACKGROUND: Heavy menstrual bleeding (HMB) has been shown to have a profound negative impact on women's quality of life and lead to increases in health care costs; however, data on HMB among Chinese population is still rather limited. The present study therefore aimed to determine the current prevalence and risk factors of subjectively experienced HMB in a community sample of Chinese reproductive-age women, and to evaluate its effect on daily life. METHODS: We conducted a questionnaire survey in 2356 women aged 18-50 years living in Beijing, China, from October 2014-July 2015. A multivariate logistic regression model was used to identify risk factors for HMB. RESULTS: Overall, 429 women experienced HMB, giving a prevalence of 18.2%. Risk factors associated with HMB included uterine fibroids (adjusted odds ratio [OR] =2.12, 95% confidence interval [CI] = 1.42-3.16, P < 0.001) and multiple abortions (≥3) (adjusted OR = 3.44, 95% CI = 1.82-6.49, P < 0.001). Moreover, women in the younger age groups (≤24 and 25-29 years) showed higher risks for HMB, and those who drink regularly were more likely to report heavy periods compared with never drinkers (adjusted OR = 2.78, 95% CI = 1.20-6.46, P = 0.017). In general, women experiencing HMB felt more practical discomforts and limited life activities while only 81 (18.9%) of them had sought health care for their heavy bleeding. CONCLUSIONS: HMB was highly prevalent among Chinese women and those reporting heavy periods suffered from greater menstrual interference with daily lives. More information and health education programs are urgently needed to raise awareness of the consequences of HMB, encourage women to seek medical assistance and thus improve their quality of life.

Gonadal tumour risk in 292 phenotypic female patients with disorders of sex development containing Y chromosome or Y-derived sequence.

OBJECTIVE: Phenotypic female disorders of sex development (DSD) patients with Y chromosome or Y-derived sequence have an increased risk of gonadal germ cell tumours (GCTs). The objective of the study was to evaluate tumour risk of DSD, summarize the clinical characteristics of patients with GCTs and propose management suggestions. METHODS: Medical records of 292 patients diagnosed DSD and undergoing bilateral gonadectomy at Peking Union Medical College Hospital from January 1996 to March 2016 were retrospectively reviewed. Tumour histopathological types, risks and clinical characteristics were evaluated. RESULTS: The tumours in DSD included gonadoblastoma, seminoma, dysgerminoma, Sertoli cell tumour, yolk sac tumour and choriocarcinoma. The overall GCTs risk was 15·41% and 46, XY pure gonadal dysgenesis (46, XY PGD) carried the highest risk up to 23·33%, followed by complete androgen insensitivity syndrome (CAIS). The risk of mixed gonadal dysgenesis (GD) or 46, XY 17 alpha-hydroxylase/17, 20-lyase deficiency (46, XY 17 OHD) was <10%, and no tumour was found in five testis regression patients. The ages (years) of tumour diagnosed ranged from 11 to 29 [18 (15, 21) years]. The median age of androgen insensitivity syndrome (AIS) with tumours was comparatively late [19 (18, 24) years], while GCTs occurred during adolescence in 46, XY PGD [17 (15, 20) years] and mixed GD [15 (15, 17) years]. Sex hormone levels were generally unaffected by gonadal GCTs. The positive tumour marker rate before surgery was 58·82% (10/17). Elevated lactate dehydrogenase (LDH) was observed in six cases with dysgerminoma/seminoma. Remarkably elevated α-fetoprotein (AFP) or human chorionic gonadotropin (hCG) was seen in cases with yolk sac tumour or choriocarcinoma, respectively. Mild hyperandrogenism was observed in seven cases with GCTs. Fourteen of 17 pelvic masses found before operation was later proved malignant. CONCLUSION: Disorders of sex development patients with Y chromosome materials have a significantly increased risk of GCTs. Gonadoblastoma and dysgerminoma/seminoma are the most prevalent GCTs and 46, XY PGD carries the highest tumour presence and malignancy risk. AIS could postpone bilateral gonadectomy until or after adolescence, while others with streak gonads should undergo surgery as soon as diagnosis. Specific serum tumour markers could be used in predicting GCTs and monitoring. Optimal care and close follow-up are required.

Clinical features and management of 33 patients with 46,XX pure gonadal dysgenesis.

The objective of the study is to summarize the clinical characteristics of 33 patients' cohort (46,XX pure gonadal dysgenesis, 46,XX PGD), discuss the management, and propose treatment suggestions. Patients' information, medical history, and medical records were obtained. All patients were closely followed up. At the time of diagnosis, the patients presented 19.53 ± 3.60 years old, 165 ± 6.49 cm height, breast development of Tanner stage I, and infantile female genitalia. High level of follicle-stimulating hormone (87.41 ± 21.50 mIU/mL) and LH (27.10 ± 8.47 mIU/mL) and low level of E2 (8.85 ± 6.13 pg/mL) were observed. Individualized hormone replacement therapy (HRT) was initiated after diagnosis. After 2 years of treatment, all patients had obvious breast development; the uterus showed (2.38 ± 0.60) × (1.38 ± 0.70) × (1.38 ± 0.55) cm growth. The incidence of osteopenia changed from 69.70% to 22.22% and that of osteoporosis changed from 18.18% to 0. Dysgeminoma was found in one patient. We concluded that gonadal dysgenesis in 46,XX PGD causes secondary sexual characteristic absence, tendency of taller, osteoporosis, infertility, and sexual health problems. There is minor chance of tumor occurrence for the patients. Optimal care including HRT and close follow-up are required.

Gonadal malignancy in 202 female patients with disorders of sex development containing Y-chromosome material.

The objective of this study was to examine risks for gonadal malignancy in a large sample of adult female patients with disorders of sex development (DSD). A retrospective-observational study was conducted from July 1992 to March 2015 and 202 women with DSD were enrolled. Tumor risks for different types of DSD were measured. We found that the patients' total gonadal-malignancy risk was 18.3% (37/202). Tumors included gonadoblastoma (n = 11), seminoma (n = 8), dysgerminoma (n = 5), choriocarcinoma (n = 1), sertoli cell tumors (n = 11), and leydig cell tumors (n = 1). The incidence of gonadal malignancy in patients with complete androgen insensitivity syndrome (CAIS), pure 46, XY gonadal dysgenesis, 45 X/46 XY mixed gonadal dysgenesis, 17α-hydroxylase/17, 20-lyase deficiency and partial androgen insensitivity syndrome (PAIS) were 27.1% (13/48), 22.4% (15/67), 10.9% (5/46), 10% (2/20) and 9.5% (2/21), respectively. Our results suggest that the incidence of gonadal malignancy increases with age for female patients with Y-chromosome material. Upon diagnoses, immediate, prophylactic gonadectomies should be considered for adult female patients with DSD containing Y chromosome material if they cannot receive regular follow-ups.

Clinical Features of 32 Patients with XO/XY Gonadal Dysgenesis.

Objective To summarize the clinical features of XO/XY gonadal dysgenesis. Method We retrospectively analyzed the clinical data of patients with XO/XY gonadal dysgenesis admitted to Peking Union Medical College Hospital from January 2008 to May 2015. Results Totally 32 patients with XO/XY gonadal dysgenesis were included. The social gender was female in all subjects and the age 6 to 33 years. Patients presented mainly with primary amenorrhea or short stature,and usually had specific somatic signs of Turner's syndrome. The breast development of 27 patients (84.38%) was less than level 3. The armpit hair was sparse or absent in 28 patients (87.5%) and the pubic hair was sparse or absent in 26 patients (81.25%).Other findings include naive vulva (n=18,56.25%)) and enlarged clitoris (n=5,15.63%). The average level of follicle stimulating hormone was (78.56±35.62) mIU/ml,the luteinizing hormone level was (20.23±11.35) mIU/ml,the estradiol level was (9.94±8.21) pg/ml,and the testosterone level was (0.24±0.18) ng/ml. All patients received prophylactic gonadectomy. The histopathology results showed a variety of gonads,and gonadal malignancy were observed in 4 patients.Conclusions Patients with XO/XY gonadal dysgenesis manifest primary amenorrhea or short stature,poorly developed secondary sexual characteristics,and elevated gonadotropin level. The gonads have increased risk of gonadal malignancy.

Surgical Therapy of 17α-hydroxylase Deficiency in 30 Patients.

Objective To analyze the clinical features of 17α-hydroxylase deficiency and explore the appropriate timing and methods of surgical treatment. Methods We retrospectively analyzed the clinical data of patients with complete 17α-hydroxylase deficiency,containing Y chromosome material in their karyotype,adimitted to Peking Union Medical College Hospital from January 2004 to December 2014. Results Thirty patients with complete 17α-hydroxylase deficiency were included. Their social gender were all female and the mean age at diagnosis was (16.1±2.7) years. Twenty-six patients (86.7%) presented with primary amenorrhea and hypertension. The development of secondary sexual characteristics was poor and their uterus was absent. The levels of gonadotropin,progesterone,and adrenocorticotropic hormone were elevated in all patients and the levels of estradiol,testosterone,and cortisol were decreased. All patients had undergone laparoscopic gonadectomy. Most (86.7%) of the gonads were located in abdomen,while 13.3% were in inguinal canal. Histopathology confirmed that gonadal malignancy was obsetved in two patients (6.7%): one with leydig cell tumor and the other with sertoli cell tumor. Conclusions Patients with complete 17α-hydroxylase deficiency have specific clinical features. Early diagnosis and timely laparoscopic gonadectomy are critical to prevent gonadal malignancy.

[Change tendency during 30 years of infertility and endometriosis in Peking Union Medical College Hospital].

OBJECTIVE: To analyze the incidence of endometriosis in inpatients with infertility in Peking Union Medical College Hospital in 30 years. METHODS: The inpatients of Peking Union Medical College Hospital admitted between May 1983 and November 2013 was searched. The infertile patients receiving laparoscopy or laparotomy were included. The discharge diagnosis and the operation were summarized. The incidence of gynecologic diseases were demonstrated, such as endometriosis, pelvic adhesions, uterine fibroid, hydrosalpinx, ovarian benign tumor, and adenomyosis. The age was collected, and the change of age and the incidence of endometriosis was analyzed. RESULTS: The incidence of endometriosis in infertile female inpatients was 35.50% (95% CI: 34.50%-36.49%). The incidence showed relatively stable increasing tendency after 2004 (with P < 0.01). The age had increased significantly since 1996 (with P < 0.01); the average age was (29.76 ± 3.74) years old in 1996, and (32.85 ± 4.49) years old in 2013 (P < 0.01). The inpatients diagnosed with endometriosis had greater age, (32.67 ± 4.06) versus (32.04 ± 4.55) years old (P < 0.01); the incidence of endometriosis differed in different age group, the older group had higher incidence (χ² = 85.807, P < 0.01). CONCLUSIONS: Infertile female inpatients showed increasing incidence of endometriosis in recent years. Older infertile patients maybe have higher risk of endometriosis.

Practice guideline on ovarian tissue cryopreservation and transplantation in the prevention and treatment of iatrogenic premature ovarian insufficiency.

Premature ovarian insufficiency (POI) refers to the decline of ovarian function before the age of 40. POI causes a reduction in or loss of female fertility, accompanied by different degrees of menopausal symptoms, which increases the risk of chronic diseases related to early menopause and seriously affects patients' quality of life and health. It is conservatively estimated that at least one million prepubertal girls and women of reproductive age in China are at risk of iatrogenic POI caused by radiotherapy and chemotherapy every year. With the development of medical technology and the breakthrough of scientific and technological advances, preventing and treating iatrogenic POI have become possible. International and national guidelines consider cryopreserved ovarian tissue transplantation to be the most promising method of preserving the ovarian function and fertility of prepubertal girls and women of reproductive age who cannot delay radiotherapy and chemotherapy. In order to guide the clinical application of ovarian tissue cryopreservation and transplantation technology in China, the Guideline Working Group finally included 14 scientific questions and 18 recommendations through a questionnaire survey, field investigation, and consultation of a large number of Chinese and English literature databases in order to provide a reference for colleagues in clinical practice.

CYP17A1 mutations identified in 17 Chinese patients with 17α-hydroxylase/17,20-lyase deficiency.

CONTEXT: 17α-hydroxylase deficiency (17OHD) is a relatively rare disease, accounting for about 1% of congenital adrenal hyperplasia cases. The CYP17A1 gene mutation can lead to this disease. Human CYP17A1 gene is located on chromosome 10q24.3. It consists of eight exons encoding 508 amino acids. To date, more than 50 mutations in exons and introns of the CYP17A1 gene have been reported to cause complete or partial 17OHD. OBJECTIVE: The aim of this study was to investigate the CYP17A1 gene mutation types in 17 Chinese patients, containing 11 complete and six partial 17OHD patients. SETTING: We conducted the study in the Department of Obstetrics and Gynecology of Peking Union Medical College Hospital. PATIENTS: Seventeen patients were studied with complete or partial 17OHD. MAIN OUTCOME MEASURES: The CYP17A1 gene was sequenced and we measured steroid and sex hormone levels. RESULTS: Analysis of the CYP17A1 gene in our patients revealed 12 different kinds of mutation. Two mutations (IVS1-1G>A and L209P) were novel mutations. Mutation c.985_987delTACinsAA (Y329KfsX418) in Exon 6 was the most common mutation in Chinese patients, accounting for 50 percents of the mutant alleles (17/34). Exon 6 was the hot spot since most mutations were detected in this exon (59%, 20/34 alleles). There was no mutation detected in the Exons 4 and 5.

Diagnostic challenges and management advances in cytochrome P450 oxidoreductase deficiency, a rare form of congenital adrenal hyperplasia, with 46, XX karyotype.

Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype-genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients' outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility.

A deletion variant Arg616 of androgen receptor in a Chinese family with complete androgen insensitivity syndrome.

Background: Complete androgen insensitivity syndrome (CAIS, OMIM; 300068) is a disorder of sex development with X-linked recessive inheritance. Cases of CAIS usually present as female phenotype, with primary amenorrhea and/or inguinal hernia. Family aggregation is a rare scenario. Methods: This study is a retrospective analysis of CAIS cases in a three-generation pedigree. The patients' genomes were determined by sequencing the androgen receptor (AR) gene. The clinical data of the patients, including manifestations, hormone levels, and AR variants, were analyzed. Results: Sixteen people in this family were involved. A deletion variant (c.1847_1849del; p. Arg616del) was identified in exon 3 of AR, which encodes the DNA binding domain. Until now, four patients and four carriers have been identified in three generations of this family. All the patients live as female, and one has developed gonadal malignancy. Conclusion: The present study identified a deletion variant in three generations of a family with CAIS, including four carriers and four patients. This study verified the genetic pattern and the corresponding clinical characteristics of CAIS. Furthermore, a case with gonadal malignancy was discovered. The information on diagnosis and treatment in this pedigree is useful for prenatal diagnosis and genetic counseling of similar families.

Molecular study of five Chinese patients with 46XX partial 17a-hydroxylase/17,20-lyase deficiency.

CONTEXT: Partial 17a-hydroxylase/17,20 lyase deficiency (17OHD) is a rare subtype of 17OHD caused by CYP17 gene mutations. OBJECTIVE: Five Chinese 46,XX patients and one family with partial 17OHD were genotyped. PATIENTS: The five patients derived from different families and one of them had another patient in family. The diagnosis of partial 17OHD was established through clinical and laboratory characteristics in Peking Union Medical College Hospital, China, from 2000 to 2010. RESULTS: Seven CYP17 gene mutations are identified from these patients. Among them, R449C and L209P are two novel missense mutations. Four patients are found to have a compound heterozygous mutations and one patient has only one mutation. The patients with family history are also found to have parent origin of gene mutations. CONCLUSION: Two novel missense mutations in CYP1 7 are found in this study. Comparing with previous reports, the different combination of mutations may have various effects on the activities of the 17-hydroxylase and/or17,20-lyase.

[Clinical study on 48 cases with complete 17α-hydroxylase deficiency].

OBJECTIVE: To investigate efficient diagnosis and treatment of 17α-hydroxylase (17OHD) deficiency by summarizing clinical characteristics of those patients. METHODS: From January 1983 to January 2010, 48 cases with 17OHD in Peking Union Medical College Hospital were studied retrospectively. RESULTS: Among 48 patients with 17OHD, karyotype analysis showed, 12 cases with 46, XX and 36 cases with 46, XY. The 46, XX karyotype and 46, XY karyotype with complete 17OHD had typical clinical presentation of amenorrhea[12/12, 100% (36/36)], no typical spontaneous puberty [12/12, 13.9% (5/36)], Hypertension [11/12, 100% (36/36)], hypokalemia [K(+): (2.6 ± 0.7), (2.8 ± 0.7) mmol/L], hypergonadotropin [follicle-stimulatinghormone (FSH): (51 ± 35), (79 ± 46) U/L, luteinizing hormone (LH): (27 ± 14), (49 ± 37) U/L], impaired production of sex hormones [testosterone (T): 0.003, 0.005 nmol/L; estradiol (E(2)): 26.86, 10.64 pmol/L], hyper-progesterone[ (P): (32 ± 15), (29 ± 23) nmol/L], impaired production of 17α-hydroxyprogesterone (17α-OHP)[(2.5 ± 1.1), (2.4 ± 1.7) nmol/L], ACTH hypersecreation (91.8, 114.0 pmol/L). ACTH stimulating test did not elevated in 17α-OHP and cortisol. CONCLUSION: When patients with elevated basal serum levels of progesterone higher than that of ovulation period in addition to clinical symptoms, examination about 17OHD should be warranted.

Ovarian gonadoblastoma with dysgerminoma in a girl with 46,XX karyotype 17a-hydroxylase/17, 20-lyase deficiency: A case report and literature review.

17α-hydroxylase/17,20-lyase deficiency (17-OHD), caused by mutations in the gene of the cytochrome P450 family 17 subfamily A member 1 (CYP17A1), is a rare type of congenital adrenal hyperplasia (CAH), usually characterized by cortisol and sex steroid deficiency combined with excessive mineralocorticoid. Gonadoblastoma is a relatively rare ovarian tumor that is frequently seen among patients with 46,XY gonadal dysgenesis. Rarely have they been reported in female patients with normal 46,XX karyotype. Here, we report an interesting case of an 11-year-old Chinese girl who presented acute abdominal pain that was later attributed to tumor rupture of right ovarian gonadoblastoma with dysgerminoma. Further evaluations revealed hypertension and hypokalemia. Hormonal findings showed increased progesterone, hypergonadotropic hypogonadism, and low cortisol levels. Her chromosome karyotype was 46,XX without Y chromosome material detected. Genetic analysis revealed that the patient had a homozygous pathogenic variant c.985_987delTACinsAA (p.Y329Kfs*90) in exon 6 of the CYP17A1 gene and that her parents were all heterozygous carriers of this pathogenic variant. Due to the variable clinical manifestations of 17-OHD, meticulous assessment including genetic analysis is necessary. Further study is warranted to unravel the mechanism of gonadoblastoma in a patient with normal karyotypes.

Clinical characteristics and molecular etiology of partial 17α-hydroxylase deficiency diagnosed in 46,XX patients.

Introduction: Complete 17α-hydroxylase deficiency (17OHD) is relatively common, with typical juvenile female genitalia, severe hypertension, hypokalemia, and the absence of sexual development, but partial (or non-classical) 17OHD (p17OHD) is extremely rare. The p17OHD patients can present with a broad spectrum of symptoms in 46,XX karyotype including various degree of spontaneous breast development after puberty, recurrent ovarian cysts, oligomenorrhea and infertility depending on specific gene mutations and other influencing factors. Methods: This paper is a retrospective analysis of p17OHD cases from 1997 to 2021 in a Chinese tertiary hospital. Eight patients were recruited from unrelated families according to clinical data. Genotypes of patients were determined by sequencing the CYP17A1 genes. Clinical characteristics were summarized based on manifestations, hormone profiles, and responses to treatments. Results: All seven post-pubertal patients had abnormal menses. All patients had enlarged multilocular ovaries, and six (6/8) had a history of ovarian cystectomy prior to a definite diagnosis of p17OHD. All eight patients' sex hormone levels were in accord to hypogonadism with mildly elevated follicle-stimulating hormone levels, and oral contraceptives effectively suppressed the ovarian cysts. Of the four patients who underwent plasma renin activity tests, all showed results below the reference range. Fourteen alleles with a CYP17A1 mutation were found. Exon 6 was the most frequent mutation site (5/14), and four out of these five mutations were c.985_987delTACinsAA, being the most common one. In Case 2, c.1220dupA was a newly reported mutation of CYP17A1. Conclusions: 46,XX p17OHD patients were born with highly fragile ovarian reserve due to diverse mutations of CYP17A1. However, their multi-ovarian cysts can be managed conservatively for fertility preservation. This study focuses on p17OHD in 46,XX by locating the complex genetic causes in novel mutations, summarizing the puzzling spectrum of clinical manifestations, and illustrating the significance of fertility preservation in these scarce cases.

Genotype-Phenotype Correlation Analysis and Identification of a Novel SRD5A2 Mutation in Four Unrelated Chinese Patients with 5α-Reductase Deficiency.

Objective: The 5α-reductase type 2 deficiency is mainly caused by mutations in the SRD5A2 gene. Our study aims to investigate the SRD5A2 gene mutations and their corresponding manifestations. Methods: Four unrelated Chinese patients with 46, XY ambiguous genitalia were studied. Molecular genetic alterations and clinical presentations were analyzed. Results: Five variants in the SRD5A2 gene were identified, all highly conserved in vertebrate orthologs. The p.P251A was a novel variant, predicted to "Affect protein function" and to be "probably damaging". Combining patients' gene mutations with their external genitalia and male sexual characteristics, we found that three variants, p.Q6X, p.N193S, and p.H90Y, were associated with severe undervirilization of external genitalia, and the other two, p.G203S and p.P251A, probably retained part of the enzyme activity. Conclusion: Mutation analysis of SRD5A2 gene is crucial for differential diagnosis in patients with 5α-reductase type 2 deficiency. Patients' variable manifestations depend on the mutation type and residual enzyme activity. The novel variant p.P251A enlarges the spectrum of SRD5A2 mutations.

[Relationship between endometriosis fertility index and pregnancies after laparoscopic surgery in endometriosis-associated infertility].

OBJECTIVE: To evaluate the relationship between endometriosis fertility index (EFI) and pregnancies after laparoscopic surgery in endometriosis-associated infertility. METHODS: From Jan. 2005 to Jan. 2010, medical documents of 350 infertile patients due to endometriosis undergoing laparoscopic surgery were studied retrospectively. Pregnancy outcomes were followed up by telephone. EFI was calculated by history factors, least function score and some aspects of the revised American Fertility Society (r-AFS) endometriosis stage. The cumulative pregnancy rate was calculated and compared by Kaplan-Meier survival analysis. RESULTS: Within 3 years after surgery, the cumulative pregnancy rates among patients with EFI score 8, 9, 10 were 62.5%, 69.8% and 81.1%, respectively. There was no significant difference in pregnancy rates among those three groups of patients (P = 0.24). The cumulative pregnancy rates among patients with EFI score 5, 6, 7 were 49.8%, 43.9% and 41.6%, respectively, which did not reach statistical difference (P = 0.83). The cumulative pregnancy rates of EFI score 8 - 10 was significantly higher than that of EFI score 5 - 7 (71.8% vs. 44.4%, P = 0.000). The patients with EFI score 0 - 4 was quite small with only 33 cases, among which 15 cases were pregnant. CONCLUSIONS: There is relationship between EFI and pregnancy in patients with endometriosis-associated infertility. EFI is meaningful to guide post-surgical treatment.