Mode of delivery of women with Swyer syndrome in a German case series.

OBJECTIVES: For women with Swyer Syndrome, a 46,XY gonadal dysgenesis, full term pregnancies are possible after oocyte donation. According to literature, mode of delivery is almost always by Caesarean section for various reasons. Medical indications are multiple pregnancies and related complications, preeclampsia, an androgynous shaped pelvis and failed induction of labor. Elective Caesarean sections were performed based on maternal request and medical recommendation. METHODS: Following careful examination and shared decision making, we planned a spontaneous delivery with a patient with Swyer syndrome and tested the different hypotheses regarding anatomical and functional features according to literature. In addition, deliveries of women with Swyer Syndrome were analyzed in a German multicenter case series. RESULTS: A total of seven women with Swyer syndrome with a total of 10 pregnancies were identified, who later gave birth to twelve live-born children. Seven out of 10 births were performed by elective and non-elective Caesarean section, three births took place vaginally. CONCLUSIONS: In summary, the risk of Caesarean section delivery has increased, but spontaneous delivery can be attempted in the event of inconspicuous findings.

Breast Cancer and Major Deviations of Genetic and Gender-related Structures and Function.

We have searched the literature for information on the risk of breast cancer (BC) in relation to gender, breast development, and gonadal function in the following 8 populations: 1) females with the Turner syndrome (45, XO); 2) females and males with congenital hypogonadotropic hypogonadism and the Kallmann syndrome; 3) pure gonadal dysgenesis (PGD) in genotypic and phenotypic females and genotypic males (Swyer syndrome); 4) males with the Klinefelter syndrome (47, XXY); 5) male-to-female transgender individuals; 6) female-to-male transgender individuals; 7) genotypic males, but phenotypic females with the complete androgen insensitivity syndrome, and 8) females with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (müllerian agenesis). Based on this search, we have drawn 3 major conclusions. First, the presence of a Y chromosome protects against the development of BC, even when female-size breasts and female-level estrogens are present. Second, without menstrual cycles, BC hardly occurs with an incidence comparable to males. There is a strong correlation between the lifetime number of menstrual cycles and the risk of BC. In our populations the BC risk in genetic females not exposed to progesterone (P4) is very low and comparable to males. Third, BC has been reported only once in genetic females with MRKH syndrome who have normal breasts and ovulating ovaries with normal levels of estrogens and P4. We hypothesize that the oncogenic glycoprotein WNT family member 4 is the link between the genetic cause of MRKH and the absence of BC women with MRKH syndrome.

Observational study of disorders of sex development in Yaounde, Cameroon.

Introduction According to the current classification of the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) of Disorders of Sex Development (DSD), etiologies vary around the world. Ethnic or genetic diversity probably explains this variability. We therefore conducted the present study on etiologies of DSDs in a country from central Africa. Methods We carried out an observational retrospective study at the Pediatric Endocrinology Unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde, Cameroon from May 2013 to December 2019. All patients diagnosed with a DSD were included, and incomplete files excluded. Results We included 80 patients diagnosed with DSD during the study period. The 46,XX DSD were the most frequent in our study population (n = 41, 51.25%), with congenital adrenal hyperplasia (CAH) as the main diagnosis. The 46,XY DSD accounted for 33.75% and sex chromosome DSD group represented 15% of the study population. Conclusions DSDs are not an exceptional diagnosis in a Sub-Saharan context. 46,XX DSD are the most prevalent diagnosis in our setting. The diagnosis of all these affections is late compared to other centers, justifying advocacy for neonatal screening of DSDs in our context.

Chromosomal aberrations in women with primary and secondary amenorrhea: A cross-sectional study.

AIM: Among women of childbearing age, about 2-5% are affected by amenorrhea that is either primary or secondary. However, there are no data regarding the frequency and type of chromosomal abnormalities associated with amenorrhea in Saudi women. The present study aims to establish the frequency and pattern of chromosomal abnormalities in primary amenorrhea (PA) and secondary amenorrhea (SA) cases in a tertiary care center, Riyadh, Saudi Arabia. METHODS: This cross-sectional study was conducted between 2013 and 2016 on women referred to the Reproductive Endocrine and Infertility Medicine Department at a tertiary care center in Riyadh. Women were divided into two groups: PA and SA. After the initial diagnosis of amenorrhea based on medical history, physical examination, hormonal profile and ultrasonography, chromosome karyotype analysis was conducted on metaphase preparations following routine cytogenetics culture and harvest methods. RESULTS: Chromosomal tests were performed for 53 patients (42 with PA and 11 with SA) out of 79 referred patients with amenorrhea. About 19% of the 42 patients with PA and 1 patient (9.1%) diagnosed as SA showed an abnormal karyotype. The most common abnormal karyotypes observed were 46, XY and 45, X. CONCLUSION: The present study indicates that the chromosomal analysis after the exclusion of nongenetic causes should be essentially considered for the precise diagnosis and the development of more successful management for females with amenorrhea. This study also revealed that the prevalence of chromosomal abnormalities in women with PA and SA is similar to that reported in the literature.

Clinical but Not Histological Outcomes in Males With 45,X/46,XY Mosaicism Vary Depending on Reason for Diagnosis.

CONTEXT: Larger studies on outcomes in males with 45,X/46,XY mosaicism are rare. OBJECTIVE: To compare health outcomes in males with 45,X/46,XY diagnosed as a result of either genital abnormalities at birth or nongenital reasons later in life. DESIGN: A retrospective, multicenter study. SETTING: Sixteen tertiary centers. PATIENTS OR OTHER PARTICIPANTS: Sixty-three males older than 13 years with 45,X/46,XY mosaicism. MAIN OUTCOME MEASURES: Health outcomes, such as genital phenotype, gonadal function, growth, comorbidities, fertility, and gonadal histology, including risk of neoplasia. RESULTS: Thirty-five patients were in the genital group and 28 in the nongenital. Eighty percent of all patients experienced spontaneous pubertal onset, significantly more in the nongenital group (P = 0.023). Patients were significantly shorter in the genital group with median adult heights of 156.7 cm and 164.5 cm, respectively (P = 0.016). Twenty-seven percent of patients received recombinant human GH. Forty-four patients had gonadal histology evaluated. Germ cells were detected in 42%. Neoplasia in situ was found in five patients. Twenty-five percent had focal spermatogenesis, and another 25.0% had arrested spermatogenesis. Fourteen out of 17 (82%) with semen analyses were azoospermic; three had motile sperm. CONCLUSION: Patients diagnosed as a result of genital abnormalities have poorer health outcomes than those diagnosed as a result of nongenital reasons. Most patients, however, have relatively good endocrine gonadal function, but most are also short statured. Patients have a risk of gonadal neoplasia, and most are azoospermic, but almost one-half of patients has germ cells present histologically and up to one-quarter has focal spermatogenesis, providing hope for fertility treatment options.

Morbidity, Mortality, and Socioeconomics in Females With 46,XY Disorders of Sex Development: A Nationwide Study.

Context: Little is known about long-term health outcomes in phenotypic females with 46,XY disorders of sex development (XY females), and the socioeconomic profile has not been described in detail. Objective: To describe morbidity, mortality, and socioeconomic status in XY females in a comparison to the general population. Design: Nationwide registry study with complete follow-up. Setting: Uniform public health care system. Participants: A total of 123 XY females karyotyped in Denmark during 1960 to 2012 and a randomly selected age-matched control cohort of 12,300 females and 12,300 males from the general population. Main Outcome Measures: Overall mortality and morbidity as well as cause-specific morbidity; medicine use and socioeconomics (education, income, cohabitation, motherhood, and retirement). Results: Compared with female controls, overall morbidity was increased in XY females [hazard ratio (HR), 1.72; 95% confidence interval (CI), 1.43 to 2.08] but not when excluding diagnoses associated with the specific disorder of sex development (DSD) diagnosis or pregnancy and birth (HR, 1.13; CI, 0.93 to 1.37). Mortality was similar to controls (HR, 0.79; CI, 0.35 to 1.77). Cohabitation (HR, 0.44; CI, 0.33 to 0.58) and motherhood (HR, 0.10; CI, 0.05 to 0.18) were reduced in XY females but education (HR, 0.92; CI, 0.61 to 1.37) was similar to controls. Income was higher than among controls in the older years. Conclusions: Morbidity was not increased in XY females when excluding diagnoses associated to the DSD condition per se. Judged on education and income, XY females perform well in the labor market. However, DSD seems to impact on the prospects of family life.

Etiology and management of primary amenorrhoea: A study of 102 cases at tertiary centre.

OBJECTIVE: To determine the prevalence of etiologic causes of primary amenorrhea in Indian population. MATERIALS AND METHODS: A retrospective study was performed using 102 complete medical records of women with primary amenorrhea who attended the Gynaecologic Endocrinology Clinic, Department of Obstetrics and Gynaecology, AIIMS, New Delhi from September 2012 to September 2015. Cases were analysed according to clinical profile, development of secondary sexual characteristics, physical examination, pelvic and rectal examination, X-ray of chest and lumbo-sacral spine, hormone profile, pelvic USG, MRI, and cytogenetic study including karyotype. RESULTS: The three most common causes of primary amenorrhea were Mullerian anomalies (47%), gonadal dysgenesis (20.5%), and hypogonadotropic hypogonadism (14.7%) in the present study. There were 3 cases of Turner syndrome (45,XO), 5 cases of Swyer's syndrome (46,XY) and 2 cases of Androgen insensitivity syndrome (46,XY). One case had pituitary macroadenoma and eight cases (7.8%) were of genital tuberculosis. CONCLUSIONS: The present study has currently been the largest case series of primary amenorrhea from North India. Mullerian anomaly is the most prevalent etiological factor leading to amenorrhoea followed by gonadal dysgenesis in our study. Racial, genetic and environmental factors could play role in the cause of primary amenorrhea.

Clinical heterogeneity in children with gonadal dysgenesis associated with non-mosaic 46,XY karyotype.

INTRODUCTION: Gonadal dysgenesis is unique in disorders of sex development (DSD), in that it can be associated with 46,XX, 46,XY or mosaic 45,X/46,XY karyotypes. Gonadal dysgenesis can be partial or complete. Gonadal dysgenesis associated with the Y-chromosome has increased risk of gonadal germ cell neoplasms. Most of the literature focus on 45,X/46,XY gonadal dysgenesis, while there are scanty data on the condition when the karyotype is non-mosaic 46,XY. OBJECTIVE: To investigate the diversity of clinical pictures of children presenting with 46,XY DSD due to gonadal dysgenesis. METHODS: A retrospective study on consecutive patients diagnosed with 46,XY gonadal dysgenesis at age ≤18 years in a tertiary center from 1985 to 2015. The clinical presentations, phenotypes, gonadal features and associated anomalies were investigated. RESULTS: Twenty-eight patients with Y-chromosome gonadal dysgenesis were identified during the study period and six (21.4%) had non-mosaic 46,XY karyotype. Three had complete gonadal dysgenesis (CGD) with normal female phenotype, while the other three had partial gonadal dysgenesis (PGD). Of the three patients with CGD, two presented with the classical Swyer syndrome at adolescence, while the third presented at birth with multiple congenital anomalies. The three PGD patients presented with ambiguous genitalia at birth (n = 2), and isolated hypospadias (n = 1), which was associated with Frasier syndrome. Three patients had germ cell neoplasms: bilateral gonadoblastoma (n = 1), bilateral intratubular germ cell neoplasia unclassified (n = 1), and dysgerminoma + gonadoblastoma (n = 1). Two patients had global developmental delay with other congenital anomalies, and another patient had learning difficulties with borderline intelligence (Table). DISCUSSION: The findings suggest that 46,XY gonadal dysgenesis is much rarer than 45,X/46,XY gonadal dysgenesis. Patients differed in their clinical presentations and well-established syndromes happened in half of them. Overall, the risk of germ cell neoplasms and the association with other somatic anomalies appeared to be high. The study was limited by: its small number, single-center experience, and the possibility of missing the diagnosis in some male patients with mild undervirilization. CONCLUSION: Heterogeneity was noted in the clinical, phenotypic and gonadal features among pediatric patients with 46,XY gonadal dysgenesis.

Familial forms of disorders of sex development may be common if infertility is considered a comorbidity.

BACKGROUND: Families with 46,XY Disorders of Sex Development (DSD) have been reported, but they are considered to be exceptionally rare, with the exception of the familial forms of disorders affecting androgen synthesis or action. The families of some patients with anorchia may include individuals with 46,XY gonadal dysgenesis. We therefore analysed a large series of patients with 46,XY DSD or anorchia for the occurrence in their family of one of these phenotypes and/or ovarian insufficiency and/or infertility and/or cryptorchidism. METHODS: A retrospective study chart review was performed for 114 patients with 46,XY DSD and 26 patients with 46,XY bilateral anorchia examined at a single institution over a 33 year period. RESULTS: Of the 140 patients, 25 probands with DSD belonged to 21 families and 7 with anorchia belonged to 7 families. Familial forms represent 22% (25/114) of the 46,XY DSD and 27% (7/26) of the anorchia cases. No case had disorders affecting androgen synthesis or action or 5 α-reductase deficiency. The presenting symptom was genital ambiguity (n = 12), hypospadias (n = 11) or discordance between 46,XY karyotyping performed in utero to exclude trisomy and female external genitalia (n = 2) or anorchia (n = 7). Other familial affected individuals presented with DSD and/or premature menopause (4 families) or male infertility (4 families) and/or cryptorchidism. In four families mutations were identified in the genes SRY, NR5A1, GATA4 and FOG2/ZFPM2. Surgery discovered dysgerminoma or gonadoblastoma in two cases with gonadal dysgenesis. CONCLUSIONS: This study reveals a surprisingly high frequency of familial forms of 46,XY DSD and anorchia when premature menopause or male factor infertility are included. It also demonstrates the variability of the expression of the phenotype within the families. It highlights the need to the physician to take a full family history including fertility status. This could be important to identify familial cases, understand modes of transmission of the phenotype and eventually understand the genetic factors that are involved.

Incidence, Prevalence, Diagnostic Delay, and Clinical Presentation of Female 46,XY Disorders of Sex Development.

CONTEXT: The prevalence of phenotypic females with a 46,XY karyotype is low, thus current knowledge about age and clinical presentation at diagnosis is sparse even for the most frequent conditions, androgen insensitivity syndrome (AIS), and gonadal dysgenesis. OBJECTIVE: To estimate incidence, prevalence, age at diagnosis, and clinical presentation at diagnosis in 46,XY females. DESIGN AND SETTING: A nationwide study covering all known females with a 46,XY karyotype in Denmark since 1960. The diagnosis of 46,XY disorder of sex development (DSD) was determined by medical record evaluation, data from the Danish National Patient Registry, and genetic testing, if available. PATIENTS: A total of 166 females registered as 46,XY females in the Danish Cytogenetic Central Registry were identified. RESULTS: A total of 124 females were classified as having 46,XY DSD, 78 with AIS and 25 with gonadal dysgenesis, whereas the remaining subjects had a variety of different diagnoses. The prevalence of 46,XY females was 6.4 per 100 000 live born females, and for AIS and gonadal dysgenesis, it was 4.1 and 1.5 per 100 000, respectively. Median age at diagnosis was 7.5 years (95% confidence interval, 4.0-13.5; range, 0-34 y) in AIS and 17.0 years (95% confidence interval, 15.5-19.0; range, 0-28 y) in gonadal dysgenesis (P = .001). Clinical presentation was dependent on cause of DSD. CONCLUSIONS: The first estimate on prevalence of 46,XY females is 6.4 per 100 000 live born females. The presentation of AIS and gonadal dysgenesis is distinctly different, with AIS being diagnosed during childhood and gonadal dysgenesis during pubertal years. The presenting phenotype is dependent on the cause of 46,XY DSD.

Testicular and paratesticular pathology in the pediatric population: a 20 year experience at Riley hospital for children.

The goals of this study are to define the spectrum, incidence, and relative frequency of testicular and paratesticular lesions in a typical North American population of 6 million based on the analysis of pathology specimens. Twenty years of pathology reports from 1990 to 2009 of all testicular and paratesticular specimens were retrieved and analyzed from computerized databases of the single major pediatric hospital in the state of Indiana. We showed that the three most common benign lesions were vanishing testis, atrophy/cryptorchidism, and testis torsion, all showed left-sided predominance. The incidence and trends of the major pathology entities were also studied. Neoplasms represented roughly 10% of the total, with leukemia, rhabdomyosarcoma, teratoma, and mixed germ cell tumor occurring in decreasing frequency. Many of the neoplasms occurred at characteristic narrow age ranges, with overall interesting bimodal distribution or some with unique genetic background.

Vanishing testes: a literature review.

Vanishing testes syndrome is often referred to as testicular regression syndrome (TRS) in the recent medical literature. The most characteristic histological findings are presence of a fibrovascular nodule with associated hemosiderin-laden macrophages and dystrophic calcification. Residual testicular tubules are found in less than 10% of cases, with prevalence being unrelated to age at surgery. Presence of seminiferous tubules and viable germ cells in testicular remnant tissue has been reported in some series. TRS theoretically carries a potential for malignant degeneration in the long term and therefore removal of any remnant is a common practice to eliminate this risk. However, no case series has reported germinal dysplasia or intratubular germ cell neoplasia in any of the specimens taken from these patients.

Anorchia masked by septo-optic dysplasia.

Hypogonadism affecting the male pediatric population is uncommon, with that attributed to multiple unrelated etiologies being exceedingly rare. We report a case of septo-optic dysplasia, an atypical cause of delayed puberty, with subsequent workup unveiling 2 coexistent conditions: hypogonadotropic hypogonadism and anorchia. Primary and secondary etiologies must be considered in patients with undescended testes. Thorough evaluation is mandatory to ensure proper diagnosis and care, because Occam's razor can, on unique occasions, be double-edged.

Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases.

OBJECTIVE: To determine the frequency of XY karyotypes among females with complete gonadal dysgenesis (CGD) and to investigate the frequency of both gonadal tumors and SRY mutations. DESIGN: Retrospective study based on data from all patients with CGD seen in our service from 1989 to 2010. SETTING: Clinic for disorders of sex development, University Hospital, State University of Campinas. PATIENT(S): Thirty-two patients with hypergonadotropic hypogonadism, streak gonads, internal and external female genitalia, and normal karyotype (46,XX or 46,XY); 31 were index cases and 29 did not have a previously determined karyotype. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): None. RESULT(S): The percentage of XY karyotypes among patients with CGD was 34.5% (10/29). Mean age at diagnosis among XY and XX patients was 17.4 years and 19.9 years, respectively. Gonadal tumors were found in 4 of 9 XY girls, and 7 of 10 had SRY gene mutations. CONCLUSION(S): The previously unreported finding of an elevated frequency of 46,XY karyotype among patients with CGD and the high risk of gonadal neoplasia in such cases indicate that this diagnosis must be kept in mind by clinicians and strengthen the importance of karyotype analysis in females with primary hypogonadism. In addition, the frequency of SRY mutations in XY CGD might be higher than previously considered.