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A heterozygous NR5A1 mutation is one of the most frequent causes of 46,XY DSD (disorders of sex development). We here reported a NR5A1-related 46,XY DSD patient, who first received endocrinological attention at 10 years of age for clitoromegaly. The patient had been reared as a girl, and no signs of virilization had been detected before. On examination, her clitoris was 35 mm long and 10 mm wide, with Tanner 3° pubic hair. Urogenital sinus and labial fusion was absent, while her uterus was found to be severely hypoplastic. Her basal testosterone level was 94.8 ng/dL, suggesting the presence of functioning Leydig cells. Gonadal histology revealed bilateral dysplastic testes consisting of mostly Sertoli cell-only tubules and Leydig cell hyperplasia. Novel heterozygous Arg313Leu substitution in NR5A1 was identified in the patient. Literature search confirmed twelve other cases of this scenario, namely, severe under-virilization in utero followed by spontaneous virilization around puberty in NR5A1-related 46,XY DSD. Of interest, Leydig cell hyperplasia was documented in 6 out of 9 patients for whom testicular histology was available. To keep in mind about the possible restoration of Leydig cell function around puberty, even in patients without discernible in utero androgen effect, may be of clinical significance, because it will give a great impact on the judgement about sex assignment.

A 42-year-old African man presented with hypogonadic phenotypical features, including gynoid body distribution, gynaecomastia, absent facial and truncal hair and micropenis. He denied ever experiencing development of male secondary sex characteristics. Endocrine testing revealed hypergonadotropic hypogonadism and undetectable AMH. Human chorionic gonadotropin (hCG) stimulation test failed to increase testosterone levels. Peripheral blood karyotype was 46, XY. Clinical examination and abdominal/pelvic/scrotal ultrasound and MRI failed to identify any testicular structures/remnants. Given the clinical course and the biochemical-radiological presentation, the diagnosis of bilateral anorchia was made (after more than four decades of its probable onset), and surgical exploration was decided against. The patient was subsequently started on monthly intramuscular testosterone experiencing progressive normal virilisation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with Swyer syndrome, which is also known as 46,XY pure gonadal dysgenesis, are at an increased risk of gonadoblastoma and germ cell tumor. Prophylactic gonadectomy is recommended for these patients. We report a case of stage IIA dysgerminoma arising in a streak gonad in a patient with Swyer syndrome, which was not diagnosable preoperatively and intraoperatively. The patient was primarily amenorrheic and identified as female phenotypically. She underwent gonadectomy at 27 years of age. Preoperative image analysis showed a relatively small uterus without adnexal masses. Laparoscopic findings showed bilateral streak gonads. Postoperatively, histopathological examination revealed that the patient had dysgerminoma in her left streak gonad. Preoperative and intraoperative diagnosis of dysgerminoma in normal size ovaries is thought to be difficult. Although it is rare, considering the occurrence of dysgerminoma in streak gonad with extension to the mesosalpinx, prompt prophylactic gonadectomy is strongly recommended for these patients regardless of the size of the ovaries.

The male hypogonadism-related bone mass loss is often under diagnosed. Peak bone mass is severely affected if the hypogonadism occurs during puberty and is left untreated. We present an interesting; almost bizarre case of a male with non-functional testes early during childhood and undiagnosed and untreated hypogonadism until his fifth decade of life. Forty six year male is referred for goitre, complaining of back pain. Phenotype suggested intersexuality: gynoid proportions, micropenis, no palpable testes into the scrotum, no facial or truncal hair. His medical history had been unremarkable until the previous year when primary hypothyroidism was diagnosed and levothyroxine replacement was initiated. Later, he was diagnosed with ischemic heart disease, with inaugural unstable angina. On admission, the testosterone was 0.2 ng/mL (normal: 1.7-7.8 ng/mL), FSH markedly increased (56 mUI/mL), with normal adrenal axis, and TSH (under thyroxine replacement). High bone turnover markers, and blood cholesterol, and impaired glucose tolerance were diagnosed. The testes were not present in the scrotum. Abdominal computed tomography suggested bilateral masses of 1.6 cm diameter within the abdominal fat that were removed but no gonadal tissue was confirmed histopathologically. Vanishing testes syndrome was confirmed. The central DXA showed lumbar bone mineral density of 0.905 g/cm2, Z-score of -2.9SD. The spine profile X-Ray revealed multiple thoracic vertebral fractures. Alendronate therapy together with vitamin D and calcium supplements and trans-dermal testosterone were started. Four decades of hypogonadism associate increased cardiac risk, as well as decreased bone mass and high fracture risk.

Context: There are currently no data evaluating volumetric bone mineral density (BMD), bone geometry, and body composition in adults with Klinefelter syndrome (KS) or anorchia who have been treated with T from adolescence., Objective: To determine volumetric BMD, bone geometry using peripheral quantitative computed tomography (pQCT), and body composition using dual-energy x-ray absorptiometry (DXA) in men with classical KS or anorchia treated with T from adolescence (age, <16 y), compared with matched controls., Methods: Twenty subjects (12 KS, eight anorchia) and 20 controls underwent a pQCT (66% tibia, 4% radius) and total body DXA., Results: Using adjusted regression models, there was reduced tibial cortical area (95% confidence interval [CI], -88.8 to -4.4 mm(2); P = .03) and thickness (95% CI, -0.98 to -0.10 mm; P = .02) in subjects. All other bone parameters were similar between groups. Subjects had significantly higher fat mass (95% CI, 1.6 to 14.9 kg; P = .02), trunk:leg fat ratio (95% CI, 0.09 to 0.60; P = .01), and visceral adipose mass (95% CI, 0.057 to 0.283 kg; P = .004). Lean mass was similar in both groups. Lean mass was positively associated with tibial cortical area and radial total, trabecular, and volumetric density (P < .05)., Conclusion: This first report using pQCT and DXA in men with KS or anorchia treated from adolescence showed normal volumetric BMD but reduction in cortical area and thickness, only at the 66% tibia site. Our study also demonstrated for the first time that men with KS or anorchia have increased visceral adiposity despite T treatment.

Background: 46,XY disorders of sex development (DSD) comprise a heterogeneous group of congenital conditions. Mutations in a variety of genes can affect gonadal development or androgen biosynthesis/action and thereby influence the development of the internal and external genital organs., Objective: The objective of the study was to identify the genetic cause in two 46,XY sisters of a consanguineous family with DSD and gonadal tumor formation., Methods: We used a next-generation sequencing approach by exome sequencing. Electrophysiological and high-resolution ultrasound examination of peripheral nerves as well as histopathological examination of the gonads were performed., Results: We identified a novel homozygous R124Q mutation in the desert hedgehog gene (DHH), which alters a conserved residue among the three mammalian Hedgehog ligands sonic hedgehog, Indian hedgehog, and desert hedgehog. No other relevant mutations in DSD-related genes were encountered. The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in more dysgenetic parts of the gonad. In addition, both patients suffer from a polyneuropathy. High-resolution ultrasound revealed a structural change of peripheral nerve structure that fits well to a minifascicle formation of peripheral nerves., Conclusion: Mutations in DHH play a role in 46,XY gonadal dysgenesis and are associated with seminoma formation and a neuropathy with minifascicle formation. Gonadal dysgenesis in these cases may be due to impairment of Sertoli cell-Leydig cell interaction during gonadal development.

46,XY pure gonadal dysgenesis (Swyer syndrome) is characterized by normal female genitalia at birth. It usually first becomes apparent in adolescence with delayed puberty and amenorrhea. Rarely, patients can present with spontaneous breast development and/or menstruation. A fifteen-year-old girl presented to our clinic with the complaint of primary amenorrhea. On physical examination, her external genitals were completely female. Breast development and pubic hair were compatible with Tanner stage V. Hormonal evaluation revealed a hypergonadotropic state despite a normal estrogen level. Chromosome analysis revealed a 46,XY karyotype. Pelvic ultrasonography showed small gonads and a normal sized uterus for age. SRY gene expression was confirmed by multiplex polymerase chain reaction. Direct sequencing on genomic DNA did not reveal a mutation in the SRY, SF1 and WT1 genes. After the diagnosis of Swyer syndrome was made, the patient started to have spontaneous menstrual cycles and therefore failed to attend her follow-up visits. After nine months, the patient underwent diagnostic laparoscopy. Frozen examination of multiple biopsies from gonad tissues revealed gonadoblastoma. With this report, we emphasize the importance of performing karyotype analysis, which is diagnostic for Swyer syndrome, in all cases with primary or secondary amenorrhea even in the presence of normal breast development. We also suggest that normal pubertal development in patients with Swyer syndrome may be associated with the presence of a hormonally active tumor.

A 10-month-old infant was referred for disappearance of the left testis, which had been confirmed as present on antenatal ultrasound at 38 weeks of gestation, as well as at the newborn physical exam and the 4 month exam. The right testis was enlarged, whereas the left testis was palpated as a nubbin. The right testis measured on ultrasound was 1.6 × 0.8 × 1.0 cm; the testicular volume was 0.67 cm(3). The left nubbin was hyperechoic, and accurate measurement of testicular components was difficult. At the age of 1 year 8 months, with the diagnosis of left vanishing testis, inguinal exploration was undertaken to rule out intra-abdominal cryptorchidism. A fibrous nodule that connected to the spermatic vessels and the vas deferens was resected. Histopathology indicated a testicular remnant containing seminiferous tubules, hemosiderin deposits, calcification and marked fibrosis of the stroma, suggesting hemorrhagic infarction in utero., (© 2014 Japan Pediatric Society.)

The aim of this study was to evaluate the effect of hormone therapy (HT) in the endothelial function of 46,XY disorders of sexual development (DSD) patients with female phenotype. Biochemical and ultrasound measurements were performed in 20 patients at initiation of oral 2 mg 17β-estradiol/1 mg norethisterone acetate, and after 6 months of therapy. Lipid profile, including total cholesterol (TC), LDL, HDL, triglycerides (TG) and Atherogenic Index of Plasma (AIP), as well as levels of VE-Cadherin, E-Selectin, Thrombomodulin and vWf were determined. Ultrasonographic examinations included evaluation of flow-mediated dilatation (FMD) and measurement of Carotid and Femoral Intima Media Thickness (IMT). HT raised HDL (35.4 mg/dl versus 40.1 mg/dl, p = 0.019) while lowering TG (166 mg/dl versus 109 mg/dl, p = 0.026) and AIP (0.24 versus 0.04, p = 0.007). No changes were noted in TC and LDL (215.7 mg/dl versus 192.25 mg/dl and 87.46 mg/dl versus 76.35 mg/dl, respectively). There was significant reduction of VE-Cadherin (4.05 ng/ml versus 2.20 ng/ml, p = 0.002) and E-selectin (73.98 ng/ml versus 56.73 ng/ml, p = 0.004). No change was observed in Thrombomodulin and vWf (11.76 ng/ml versus 13.90 ng/ml and 80.75% versus 79.55%, respectively). FMD improved significantly (5.4% versus 8.15%, p = 0.003), while only carotid bulb IMT decreased significantly (0.65 mm versus 0.60 mm, p = 0.018). Overall, HT was found to improve biochemical and ultrasound markers of endothelial function in 46,XY DSD patients with female phenotype.

Background: Undescended testes is one of the most common congenital abnormalities in boys. In cases of impalpable testes, ultrasound is often used to find the testis, which frequently provides false-negative results. Recently, laparoscopy has become popular in the management of impalpable testes., Methods: Retrospective study of all children with impalpable testes presenting for laparoscopy between August 2007 and July 2011 who had undergone ultrasound examinations without localizing the testes was conducted and the role of laparoscopy in diagnosing impalpable testes was evaluated., Results: Twenty-three patients presented with impalpable testes for laparoscopy. All patients underwent ultrasound examinations in which the testes could not be identified. Of the 23 patients, Five patients were found to have palpable testes in the superficial inguinal pouch under anesthesia and proceeded to conventional open exploration during which the testes were brought into the scrotum. Eighteen patients were found to have impalpable testes in an evaluation under anesthesia (EUA) and proceeded to laparoscopy. Twelve patients were found to have intra-abdominal testes and underwent laparoscopic-assisted orchidopexy. Three patients underwent a two-stage Fowler-Stephens procedure, and two patients with "vanishing" testes with the vas and atrophic vessels entering a closed internal ring proceeded to open exploration and orchidectomy for atrophic testes. In addition, a teenager with atrophic testes underwent laparoscopic orchidectomy., Conclusions: Laparoscopy is superior to ultrasound in the management of impalpable testes when high-resolution ultrasound is not available during the diagnostic process, with respect to both the sensitivity of localizing the testis and being more time and cost effective., (Copyright © 2014. Published by Elsevier B.V.)

This case of ectopic testis highlights the importance of a thorough first newborn examination followed by senior review when appropriate, and the expertise required to interpret neonatal ultrasounds. Following a provisional diagnosis of unilateral undescended testicle in a newborn, an ultrasound scan was unable to correctly identify the condition, resulting in a delay in diagnosis. The condition was later recognised incidentally, which led to a successful surgical correction. The early clinical examination and recognition of ectopic testis allows a timely surgical intervention preventing potential complications.

Objective: To determine the genetic cause of primary amenorrhea in a 46,XY woman., Design: Case report., Setting: Centre of Gynecological Endocrinology and Cytogenetics and Molecular Genetics Laboratory of university medical school., Patient(s): A 19-year-old woman referred for primary amenorrhea., Intervention(s): Clinical, endocrinologic, and ultrasonographic investigation and SRY mutation analysis., Main Outcome Measure(s): Hormone profile (LH, FSH, PRL, leptin, E(2), 17alpha-hydroxyprogesterone, 3alpha-androstanediol glucuronide), ultrasonographic evaluation, clinical follow-up., Result(s): A new SRY sporadic mutation due to a single nucleotide insertion at codon 13 position 38 (38-39insA) was found in a 46,XY woman with sex reversal. This mutation determined a frameshift of the reading frame sequence and a protein truncation at codon 16. Clinical and endocrinologic data are reported., Conclusion(s): This is a new rare case of a single nucleotide insertion affecting the SRY gene in 46,XY females with sex reversal. This new mutation should be considered in genetic counseling.

Context: The characteristics of P450c17 deficiency include 46,XY disorder of sex development, hypertension, hypokalemia, and lack of pubertal development., Objective: To better understand this rare enzymatic deficiency, we analyzed the CYP17A1 gene in six affected patients., Design and Patients: We examined six patients, five 46,XY, and one 46,XX (age 9-29 yr) with complete lack of masculinization (female infantile external genitalia, no uterus) and delayed puberty, respectively, and different degrees of hypertension., Main Outcome Measurements: Genotype-phenotype correlation was measured., Results: Four homozygote mutations were identified by direct sequencing of the CYP17A1 gene corresponding to an alanin 302-proline (A302P) exchange; the loss of lysine 327 (K327del); the deletion of glutamate 331 (E331del); and the replacement of arginine 416 with a histidine (R416H). Both P450c17 activities were abolished in all the mutant proteins, except one, when expressed in COS1 cells. The E331del-mutated P450c17 retained 17alpha-hydroxylase activity. The mutant proteins were normally expressed, suggesting that the loss of enzymatic activity is not due to defects of synthesis, stability, or localization of P450c17 proteins., Conclusion: These studies confirm lack of masculinization in 46,XY individuals as the pathognomic sign of the complete P450c17 deficiency. In XX individuals P450c17 deficiency should be considered in cases of delayed puberty. Age of onset and the severity of hypertension do not seem to be constant. Careful examination of long-term follow-ups in two of our patients suggested to us that estrogen treatment in P450c17-deficient patients might worsen the enzymatic defect, leading to aggravation of the hypertension.

Objectives: We present a case of early prenatal diagnosis of recurrent 46,XY partial gonadal dysgenesis, by combining early genetic and sonographic evaluations., Methods: The conceptus of a mother with a first child affected by 46,XY gonadal dysgenesis was sonographically evaluated at 21- and 23-mm BPD (12(+2) and 12(+6) LMP-based age) and the female genitalia were observed. Karyotype analyses was performed on amniotic fluid and it revealed a 46,XY complement without mosaicism. SRY was amplified by PCR for molecular analyses., Results: We observed a discordance between female phenotype detected at 21 and 23 mm of biparietal diameter (12(+2) and 12(+6) LMP-based age) and male karyotype. In the child and the fetus, seminiferous cords were not recognisable, whereas rare Leydig cells and no germ cells could be identified. Internal and external genitalia were sexually ambiguous in the child and feminized in the fetus., Conclusion: This is the first case of early prenatal diagnosis of recurrent 46,XY partial gonadal dysgenesis and it points to the importance of combining early analyses of genetic sex with sonography in the management of anomalies of sexual development, with particular regard to syndromes for which the risk of recurrence is little understood., (Copyright 2003 John Wiley & Sons, Ltd.)

It is described the clinical evaluation of eight cases with gonadal dysgenesis syndrome type 46XY diagnosed and followed in our division of Pediatric-Adolescent Gynecology since 1992 to January 2000. Two out of eight patients presented pure gonadal dysgenesis (Swyers syndrome), one presented 17-beta-hydroxysteroid-deydrogonase deficiency and the rest five presented Testicular Feminization Syndrome. The adolescents visited our department for the first time while being fifteen years old because of primary amenorrhea and growth retardation of secondary sex features. Apart from interview, physical and gynecological examination we performed complimentary haematological, biochemical, hormonal tests and confirmed the diagnosis by chromosomal analysis. Studying the upper and lower abdomen by the means of imaging methods (U/S and CT) we found out the presence of uterus and in few cases the gonadal position. Because of the high risk of malignancy all the patients underwent surgical gonadectomy. Postoperatively hormonal replacement therapy was administered to reinforce the female sex features and prevent the hormonal deficiency consequences like osteoporosis. The follow up included haematological, biochemical and hormonal tests. If uterus existed the endometrium thickness measured by ultrasound. Furthermore bone density, palpative and ultrasonography breast examination and investigation of possible psychological disorders insure the complete screening of the young "female" patients.

We hereby present a rare case of a 46,XY/45,XO/47,XXY mosaic male patient with a predominance of the XY cell line. The patient, who exhibited phenotypic stigmata of both XO gonadal dysgenesis and Klinefelter syndromes, suffered from infertility and multiple urogenital abnormalities, as our investigation revealed.

Swyer-James syndrome, unilateral hyperlucent lung with air entrapment, generally occurs after severe infections during childhood. It is usually diagnosed by its characteristic chest radiographic image film or computed tomography, in patients who are almost asymptomatic. We report a case of Swyer-James syndrome, diagnosed from the study of severe pulmonary hypertension and with a fatal outcome.