46,XY DSD and limb abnormalities in a female with a de novo LHX9 missense mutation.

Differences in sex development (DSD) are a group of rare conditions involving genes, hormones and reproductive organs, including genitals. Although these disorders are common, information about the molecular causes remain limited. Many genes have been identified in association with DSD but in many cases the causative gene could not be identified. The Lhx9 gene has been studied in mice and birds, and biallelic mutations in this gene have been found to cause 46,XY DSD and limb abnormalities. So far two variants of LHX9 have been identified in 46,XY individuals with testicular regression, micropenis and hypospadias. We report a de novo heterozygous missense variant in LHX9 in a girl with 46,XY DSD and finger and toe abnormalities. It was previously predicted that a mutation in LHX9 would not cause extragenital anomalies in light of prior animal studies, but our report adds to the limited knowledge of the phenotype observed in humans with a variant in LHX9. To the best of our knowledge this is the first reported case with this combination of abnormalities.

[A rare cause of cryptorchidism, the persistence of müllerian ducts syndrome]. / Une cause rare de cryptorchidie le syndrome de persistance des structures müllériennes.

The Persistent Müllerian Ducts Syndrome (PMDS) is a rare congenital syndrome. It is one of abnormalities of genito-sexual development that is found on the normally virilized boy (46XY). It is characterized by the development of both Wolf structures and Müller duct. The pathophysiology can be explained by an action deficit of the anti-müllerian hormone (AMH). Its clinical presentations vary depending on the localization of the testis and the associated symptoms. Its discovery is mostly fortuitous and generally made in per-operative surgery of cryptorchidism or inguinal hernia. Treatment should be surgical. It relies on two aspects : ensuring the testicular descent and performing the excision of the müllerian duct. The follow-up is identical to the cryptorchid testes and the fertility problems will be influenced by the surgical procedure as well as the timing of the treatment.

Le syndrome de persistance des canaux mullériens (PMDS) est un syndrome congénital rare donnant des anomalies du développement génito-sexuel chez le garçon normalement virilisé (46XY). Il se caractérise par le développement à la fois des structures de Wolf et des canaux de Müller. Sa physiopathologie s'explique par un défaut d'action de l'hormone anti-müllérienne (AMH). Il existe différentes présentations cliniques qui varient en fonction de la localisation du testicule et des symptômes associés. Sa découverte est fortuite et généralement faite en per-opératoire d'une chirurgie de cryptorchidie ou d'hernie inguinale. Le traitement doit être chirurgical. Il repose sur deux aspects : assurer la descente testiculaire et réaliser l'exérèse des canaux müllériens. Le suivi est identique à celui d'un testicule cryptorchide et le risque de trouble de la fertilité varie en fonction de l'âge de prise en charge et du geste chirurgical.

Coincidence of Persistent Müllerian duct syndrome and testicular tumors in dogs.

BACKGROUND: Persistent Müllerian duct syndrome (PMDS), a rare form of male pseudohermaphroditism in dogs, is an abnormal sexual phenotype in males that is characterized by the existence of a hypoplastic oviduct, uterus, and cranial part of the vagina. Dogs suffering from PMDS are often accompanied by cryptorchidism. To date, it has been mainly found in the Miniature Schnauzer breed. CASE PRESENTATION: In this report, two cases of PMDS with a malignant testicular tumor originating from cryptorchidism in breeds other than the Miniature Schnauzer breed are described. The patients were a seven-year-old male Maltese dog and a 17-year-old male mixed-breed dog weighing 3.8 kg. They also exhibited an enlarged prostate with or without abscess and an elevated serum estradiol level and were surgically treated to remove the testicular tumor and Müllerian duct derivatives. CONCLUSIONS: It is recommended that PMDS should be differentially diagnosed by ultrasonography and that orchiectomy be performed at an early age in patients suspected to have cryptorchidism to prevent the ectopic testes from becoming tumorous.

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.

Vaginoplasty Using Human Amniotic Membranes A Report of Five Patients.

OBJECTIVE: To present our experiences with an innovative surgical approach for vaginal agenesis that uses amnion as the allograft to create a functional neovagina. STUDY DESIGN: This study involved 5 patients with diagnosed vaginal agenesis. One patient had karyotype 46,XY and was diagnosed with complete androgen insensitivity syn- drome, whereas the others had karyotype 46,XX and were diagnosed with Mayer-Rokitansky-Kiister-Hauser syndrome. All patients underwent Mclndoe vagino- plasty using amnion and were followed up at 2 weeks, 3 months, 6 months, and 12 months postsurgery. Functionality of the neovagina was assessed by Rosen Female Sexual Function Index (FSFI) questionnaire. RESULTS: At the 12-month follow-up 1 patient report- ed. an inability to use the vaginal dilator effectively; for the other 4 patients the mean depth of the neovagina was 9.5 cm and the mean width was 3.5 cm. The mean overall FSFI score was 28.3. CONCLUSION: McIndoe vaginoplasty is a simple, safe, and quick operative method that results in a ftnctional vagina. The amnion is a suitable material to apply to the surface of the neovagina because it is readily avail- able and does not have any associated immune reiection problems or costs.

Correlation of androgen receptor and SRD5A2 gene mutations with pediatric hypospadias in 46, XY DSD children.

We performed an exploratory study by analyzing the correlation of 46, XY disorders of sex development (46, XY DSD) with androgen receptor (AR) and steroid 5α-reductase-2 (SRD5A2) gene mutations and a safety analysis of dihydrotestosterone (DHT) gel treatment for pediatric micropenis. We collected samples from 76 pediatric patients with 46, XY DSD and 50 healthy adult men with normal fertility as the control group. The pediatric patients were treated with DHT gel (0.1-0.3 mg/kg/day) for three to six months. The extended penis length, testicular volume, and multiple blood parameters were collected before treatment and one, three, and six months after treatment. Of the 76 cases with 46, XY DSD, 31.58% had hypospadias with micropenis and 6.58% had male pseudohermaphroditism. Through AR gene screening, it was found that 14 patients had AR point mutations and 22 patients had SRD5A2 mutations. After treatment with DHT, the penis length of the patients significantly improved after one, three, and six months of treatment, with longer treatment times resulting in greater improvement. Before treatment with DHT, the average serum DHT value of patients with 46, XY DSD was 24.29 pg/mL. After one, three, and six months of treatment, this value increased to 430.71, 328.9, and 323.6 pg/mL, respectively. We conclude that for pediatric patients who have male hermaphroditism or hypospadias with micropenis, AR and SRD5A2 gene mutation detection should be performed. Local application of DHT gel can promote penis growth effectively without systemic adverse reactions.

[Intra-Abdominal Germ Cell Tumor in Persistent Mullerian Duct Syndrome].

A 46-year-old man was admitted to hospital presenting with a lower abdominal mass. The patient's testes were not palpable in the scrotum, and the levels of lactic dehydrogenase, α-fetoprotein and human chorionic gonadotropin were all elevated. Enhanced computed tomography revealed that the lumen of the mass had penetrated the prostate. Pathological analysis of biopsy tissue indicated that the mass was a seminoma. Residual tumor resection was performed after chemotherapy. On histological examination, the lumen proved to be a Mullerian structure. Our diagnosis was an intra-abdominal germ cell tumor and persistent Mullerian duct syndrome.

Androgen insensitivity syndrome in a cohort of Sri Lankan children with 46, XY disorders of sex development (46, XY DSD).

INTRODUCTION: There are several conditions giving rise to 46, XY disorders of sex development (DSD) with different modes of inheritance. Therefore definitive diagnosis based on molecular genetic confirmation would be the ideal to counsel parents regarding the future implications of the condition affecting their baby. This is the first report from Sri Lanka documenting the presence of mutations in the androgen receptor (AR) gene in a cohort of children with 46, XY DSD. OBJECTIVES: To describe the socio-demographic and clinical features and document the presence of mutations in the androgen receptor (AR) gene in a cohort of children with 46, XY DSD. METHODS: 46, XY patients with ambiguous genitalia followed up in the University Unit at the Lady Ridgeway Hospital, Colombo, and clinically identified as having androgen insensitivity syndrome (AIS) or a testosterone biosynthetic defect were recruited for the study. Their socio-demographic details and clinical features were documented. Exons 1 to 8 of the AR gene were screened for mutations by DNA sequencing on a venous blood sample. SRY gene mutations were also assayed. RESULTS: Thirty-four patients were studied, 3 of whom were clinically diagnosed as having complete androgen insensitivity syndrome (CAIS). Sex of rearing was female and male in 4 and 30 respectively. AR gene mutations were detected in 6 patients (17.6%). None of the patients had SRY gene mutations. CONCLUSIONS: Majority (88%) of the patients were raised as males. Six patients (17.6%) including the 3 with CAIS, had genetically confirmed AIS with the detection of AR gene mutations.

[Persistent Müllerian ducts syndrome: one case of late hypofertility]. / Syndrome de persistance des canaux de Müller de type féminin : un cas de diagnostic tardif dans le cadre d'une infertilité

We report the case of a 35-year-old patient with a syndrome of persistent Müllerian ducts (PMDS) of the female type (group A). The diagnosis was made in adulthood during an infertility workup. Clinical examination revealed an empty scrotum, a normal penis and bilateral inguinal cystic masses. The spermogram found azoospermia. Imaging using MRI and tomotensidometry found the presence of an uterus, two fallopian tubes and two inguinal positions of polycystic testes. A surgical management was performed for surgical testicular biopsy. Histological examination then found a cystic formation of multi-celled mesothelial origin, with atrophic testis Sertoli cell involution and without sperm. PMDS is a rare form of pseudo-internal hermaphroditism characterized by the presence in a man of the uterus, fallopian tubes and upper vagina with external male genitalia and virilized characters. About 200 cases are reported in the literature. The diagnosis is often made in children intraoperatively during a cure of testicular ectopia. The karyotype is 46 XY type. The pathogenesis is related to a deficiency of anti-Müllerian hormone (AMH) or tissue resistance to its action by receptor abnormalities. The regression of the Müllerian duct derivatives can give three types of PMDS : masculine type, feminine type and a transverse type. Surgical treatment is difficult but necessary because of the risk of infertility and ectopic testicular degeneration.

[Questions and dilemmas in the management of hypospadias]. / A hypospadiasis ellátásában felmerülo kérdések, dilemmák.

Hypospadias is the second most common congenital malformation in males. Etiology remains unknown in about 70% of the cases. Distal hypospadias is considered not only developmental abnormality of the urethra in males, but it may also constitute a mild form of sexual development disorder in 46,XY males. Most urologists and endocrinologists consider that it is necessary to perform a detailed investigation of children presenting with proximal hypospadias associated with a small phallus or poorly developed scrotum and undescended testes. Currently, there is no generally accepted recommendation for the preoperative evaluation of hypospadias and, therefore, masculinizing surgery without preoperative evaluation is performed in these children. The authors summarize the international literature data and their own experience for the assessment and management of hypospadias concerning questions and problems related to preoperative investigation, masculinizing surgery and additional surgery. A detailed algorithm is presented for preoperative evaluation of both proximal and distal hypospadias.

Diagnostic and therapeutic challenges with germ cell tumours associated with transverse testicular ectopia and persistent Müllerian duct syndrome.

Transverse testicular ectopia (TTE) is an infrequent ectopic testis where both testes descend via the same inguinal canal, located in the same hemiscrotum, and augments the risk of developing testicular tumours. Type II TTE is accompanied by persistent Müllerian duct syndrome, where the Müllerian structures persist for various reasons. Here, we present a case of an adult in his early 30s, who presented with a right testicular swelling and was diagnosed as type II TTE and testicular mixed germ cell tumour after surgery. We could find only 13 similar cases of TTE and testicular tumours in the literature. Our case highlights the importance of clinical acumen with detailed history, meticulous clinical examination, radiological investigations and a detailed pathological examination while dealing with such sporadic presentations.

Clinical aspects and molecular genetics of persistent müllerian duct syndrome associated with transverse testicular ectopia: report of three cases.

Persistent müllerian duct syndrome (PMDS) is a rare form of male pseudohermaphroditism, characterized by the presence of a uterus and fallopian tubes owing to failure of müllerian duct regression in genotypically normal males. The association between a persistent müllerian duct and transverse testicular ectopia (TTE) is even more uncommon. PMDS with TTE is a very rare pathological association, often discovered during repair for inguinal hernia or cryptorchidism. We report 3 cases of Chinese patients with PMDS associated with TTE. Hysterectomy was performed, with resection of the underdeveloped fallopian tubes. Both gonads were placed into subdartos pouches in each scrotum by the transseptal approach. PMDS with TTE is a rarely encountered form of male pseudohermaphroditism usually unexpectedly found at surgery for cryptorchidism or inguinal hernia. Surgical treatment should avoid damage of fertile testes and vasa deferens.

[A case of micropenis with strong genetic basis]. / Su di un caso di micropene fortemente espresso.

The early hormonotherapy of micropenis takes on a diagnostic significance too. The very good tolerance gives value to this behaviour. The Author shows the condition of a male infant 46,XY eighteen months old; the child appeared with a micropenis completely expressed and resulting from hypogonadotropic hypogonadism. He confirms the good response to hormonotherapy for this child.

Genetic control of typical and atypical sex development.

Sex development relies on the sex-specific action of gene networks to differentiate the bipotential gonads of the growing fetus into testis or ovaries, followed by the differentiation of internal and external genitalia depending on the presence or absence of hormones. Differences in sex development (DSD) arise from congenital alterations during any of these processes, and are classified depending on sex chromosomal constitution as sex chromosome DSD, 46,XY DSD or 46,XX DSD. Understanding the genetics and embryology of typical and atypical sex development is essential for diagnosing, treating and managing DSD. Advances have been made in understanding the genetic causes of DSD over the past 10 years, especially for 46,XY DSD. Additional information is required to better understand ovarian and female development and to identify further genetic causes of 46,XX DSD, besides congenital adrenal hyperplasia. Ongoing research is focused on the discovery of further genes related to typical and atypical sex development and, therefore, on improving diagnosis of DSD.

Persistent Müllerian duct syndrome: lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the Müllerian remnants.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Approximately 200 cases of persistent Müllerian duct syndrome have been reported over the last 50 years and most authors suggest leaving the Müllerian remnant in situ because of the difficulty in dissection and the presumed absence of risk of malignancy. However, with increasing reports of Müllerian malignancies emerging, we report our 10-year experience of managing patients with persistent Müllerian duct syndrome, with removal of müllerian remnants. This case series shows that there is an increased risk of Müllerian malignancy that was previously unknown. With the laparoscopic approach, orchidopexy with simultaneous removal of Müllerian remnants could be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future. This is a new technique that has not been previously performed. Considering the current evidence of malignancy in the Müllerian remnant, surgeons would need to discuss with families about removal of remnants or long-term monitoring. OBJECTIVES: • To describe the presentation and management of eight patients with persistent Müllerian duct syndrome (PMDS) seen over a 10-year period at our tertiary centre. • To review the literature of Müllerian malignancies reported in PMDS. PATIENTS AND METHODS: • The hospital records of eight patients with PMDS were retrospectively reviewed between 2001 and 2011. • Extensive PubMed searches for PMDS and Müllerian malignancy were performed. RESULTS: • Eleven cases with PMDS and malignancy of the Müllerian remnants were identified. • From our own PMDS series: five males presented with bilateral undescended testes and three had unilateral undescended testis. • We found that the Müllerian remnants could be removed by laparoscopy and three patients had simultaneous laparoscopic removal of the Müllerian structures and laparoscopic orchidopexy. CONCLUSIONS: • The principle aim of orchidopexy with simultaneous laparoscopic removal of the Müllerian structures can be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future. • Surgeons should consider excision of the Müllerian remnants where possible.

Persistent Müllerian duct syndrome: 8 new cases in Southern California and a review of the literature.

Persistent Müllerian Duct Syndrome (PMDS) is a 46,XY disorder of sex development (DSD) in which Müllerian structures are found in genotypic males with normally virilized external genitalia and unilateral or bilateral cryptorchidism. It is usually diagnosed incidentally during surgical repair of cryptorchidism or inguinal hernia. The majority of cases are due to a mutation of the anti-Müllerian hormone (AMH) gene or the AMH receptor, type II (AMH-RII) gene. Management of patients with PMDS requires a multidisciplinary approach. Long-term prognosis is good although fertility appears to be decreased and there may be a risk of malignancy due to cryptorchidism and retained Müllerian remnants. We describe 8 new cases of PMDS diagnosed in Southern California in the past 10 years and review the literature.

[Dysgenetic male pseudohermaphroditism]. / Dysgeneticus pseudohermaphroditismus masculinus.

The authors report a case of a dysgenetic male pseudohermaphroditism with a 45,X/46,XY karyotype in a mosaic form, which was diagnosed in an infant. The one-week-old infant was evaluated because of proximal hypospadias and retention of the right testis. The results of hormonal tests were the followings: serum FSH 5.2 mU/ml; LH: 2.0 mU/ml; testosterone: 144.3 ng/dl; androstendione: 0.42 µg/l; 17-hydroxyprogesterone: 1.12 ng/ml. Chromosomal analysis revealed 45,X/46,XY karyotype. Fluorescent in vitro hybridization showed that 51% of the lymphocytes had the Y chromosome and the SRY gene. Analysis of the SRY showed no deletion in the AZF a,b,c regions. Pelvic magnetic resonance imaging indicated the presence of vagina between the bladder and the rectum, and it showed a mass measuring 15×8 mm in the right inguinal canal as well as an oval gonadal mass with a size of 13×7 mm in the left scrotum. During surgical intervention, performed at the age of one, the right gonad was removed and biopsy of the scrotal testis was performed. Histological examination revealed dysgenetic testis in both sides. The authors emphasize the necessity of cytogenetic and endocrinological investigations of newborns with perineoscrotal hypospadia and bilateral or unilateral maldescent testes immediately after birth. Surgical removal of the dysgenetic testicular tissue located in the abdominal cavity and its histological evaluation provides separation of mixed gonadal dysgenesis, dysgenetic male pseudohermaphroditism, bilateral gonadal dysgenesis and ovotestis in the 45,X/46,XY mosaic cases. An accurate evaluation is necessary for a correct sex assignment and for surgical intervention to prevent neoplastic degeneration of the dysgenetic gonad.

[Persistent Müllerian ducts syndrome]. / Syndrome de persistance des canaux de Müller.

Persistent Müllerian ducts syndrome is a rare form of internal male pseudohermaphroditism, characterized by the presence of the uterus, fallopian tubes and upper vagina in an otherwise normally virilised male with a 46 XY karyotype. It is the result of a deficiency in anti-Müllerian hormone or abnormality of this hormone receptor. Often, the diagnosis is made incidentally during surgical exploration for cryptorchidism or herniorrhaphy, and exceptionally during cancer of ectopic testis. We discuss a rare case of this syndrome revealed by a bilateral intra-abdominal gonadal tumor.

A Simplified Management of Transverse Testicular Ectopia in Patients with Persistent Mullerian Duct Syndrome.

Persistent müllerian duct syndrome (PMDS) in the majority of cases is discovered during surgery for inguinal hernia or cryptorchidism. A transverse testicular ectopia (TTE) with cryptorchidism may be very rarely associated to PMDS. Assuming that müllerian remnants have a very low malignant degeneration potential if compared to the malignancy risk of an undescended and not relocated testis, we describe a simplified surgical technique of orchiopexy that avoids an extensive anatomical dissection, in this way minimizing the risk of losing the deferential blood supply to the testis.

Detection and Treatment of Persistent Mullerian Duct Syndrome With Transverse Testicular Ectopia.

The coexistence of persistent Mullerian duct syndrome (PMDS) with transverse testicular ectopia (TTE) is extremely rare. Due to a lack of distinctive clinical features in the early stages, PMDS coexists with TTE is usuallydiagnosed when patients are examined for other diseases,including cryptorchidism and inguinal hernia. We present a case of a 51-year-old man who presented with a recurrent left indirect inguinal hernia for 2 years and right congenital cryptorchidism. The patient was diagnosed as PMDS with TTE by preoperative magnetic resonance imaging and underwent laparoscopic resection of the right transverse ectopic testis and Mullerian duct residues.