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.

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.

Non-classical lipoid adrenal hyperplasia presenting as hypoglycemic seizures.

Introduction Primary adrenal insufficiency is a potentially life-threatening condition that can have many underlying causes. Mutations in the steroidogenic acute regulatory protein (StAR) gene produce lipoid congenital adrenal hyperplasia (LCAH) which usually presents in the infantile period with severe symptoms of adrenal insufficiency. Less commonly, a non-classical form is identified which may present at a later age in affected individuals. Till date, around 30 individuals with the non-classical form have been described. Case presentation We describe a 4-year-old 46, XX Indian girl who presented with hypoglycemic seizures and was subsequently diagnosed as non-classical LCAH on genetic analysis, with homozygous R188C mutation in the StAR gene. Conclusions StAR mutations may have a variety of clinical presentations and are likely under-diagnosed. Genetic diagnosis is important for treatment as well as monitoring of reproductive function.

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.

Pregnancy and Live Birth In Women With Pathogenic LHCGR Variants Using Their Own Oocytes.

CONTEXT: The LH/chorionic gonadotropin receptor (LHCGR) is mainly expressed in gonads and plays important roles in estradiol production, ovulation, and luteal formation. Women with pathogenic LHCGR variants suffer from infertility, and successful fertility treatments for such women have never been reported. OBJECTIVE: The purpose of this study was to determine whether women with pathogenic LHCGR variants can achieve successful pregnancies through in vitro fertilization. DESIGN: Three women with LH resistance and infertility and their parents underwent exome sequencing. The biochemical characteristics and functional effects of LHCGR mutation were assessed in transfected human embryonic kidney -293T cells and primary granulosa cells. RESULTS: All affected women harbored pathogenic LHCGR variants. The LHCGR variants lacked cell surface localization and signal transduction abilities in vitro and in vivo. After dual triggering and prolonging the interval between triggering and oocyte pick-up, all three patients achieved oocytes and high-quality embryos. After frozen embryo transfer, one woman successfully birthed twins, and one woman successfully birthed a live boy. Apart from difficulties in oocyte retrieval, no obvious abnormalities in fertilization or during embryo development and pregnancy were identified in these patients. CONCLUSIONS: This study is, to our knowledge, the first to report successful assisted reproductive treatment of women with pathogenic LHCGR variants using their own oocytes. Our results supported that defects in LHCGR disrupted ovulation but had no effect on fertilization and embryo development.

A unique case of aggressive uterine cancer in a 45-year-old man withpersistent müllerian duct síndrome / Un caso único de cáncer de útero agresivo en un varón de 45 años con síndrome de persistencia del conducto de Müller

Objective: Persistent Müllerian Duct Syndrome (PMDS), one of the causes of male pseudohermaphroditism, is a rare syndrome characterized by the presence of internal female genitalia (uterus, fallopian, tubes, cervix and upper vagina) in otherwise phenotypically and normally virilized men. Methods: We present the 4th documented case of uterine malignancy in a 45-year-old man with PMDS presenting with lower abdominal protuberance and hematuria. Results: Although testicular malignancies are common in undescended testis associated with PMDS, very few cases of müllerian duct malignancies have been reported

Objetivos: El síndrome de persistencia del Conducto de Müller (SPCM), una de las causas de pseudohermafroditismo masculino, es un síndrome raro caracterizado por la presencia de genitales internos femeninos (útero, trompas de falopio, cervix y fondo vaginal) en pacientes varones fenotipicamente y con virilización normal. Métodos: Presentamos el 4º caso documentado de tumor maligno uterino en un hombre de 45 años con SPCM que presenta protuberancia abdominal inferior y hematuria. Resultados: Aunque los tumores malignos testiculares son frecuentes en testículos no descendidos asociados con SPCM, se han comunicado muy pocos casos de tumores malignos del conducto de Müller. Conclusiones: El síndrome de persistencia del Conducto de Müller se puede asociar con tumores malignos no testiculares agresivos, especialmente cáncer uterino en hombres normalmente virilizados

Unusual finding in the karyotype of a neonate with glandular hypospadias with chordee.

A 37-week, 2700 g vaginally delivered baby was admitted for respiratory distress which was attributed to transient tachypnoea of newborn. A clinical finding of glandular hypospadias with ventral chordee was detected. The penis was normal in size, and gonads were palpable bilaterally in the scrotal sac. The parents were informed of the good prognosis associated with this milder variety of hypospadias. In view of parental concerns, a fluorescent in situ hybridisation (FISH) for X and Y chromosome was performed. Surprisingly, FISH revealed the presence of 46, XY in 90% of cells and 46, XX in 10% of the remainder cells suggesting a diagnosis of chimerism.

Pubertal Development and Pregnancy Outcomes in 46,XX Patients With Nonclassic Lipoid Congenital Adrenal Hyperplasia.

CONTEXT: Lipoid congenital adrenal hyperplasia (LCAH) is characterized by a disorder of steroidogenesis in both adrenal glands and gonads. 46,XX patients with classic LCAH usually have thelarche and menarche but show anovulatory menstruations and subsequent premature menopause. Only three patients with classic LCAH have been reported to successfully achieve delivery with the aid of assisted reproductive therapies for conception and progesterone replacement therapy during early pregnancy. In contrast, pubertal development and pregnancy outcomes in patients with nonclassic LCAH have not been fully elucidated. CASE DESCRIPTION: We report four Japanese women who had a diagnosis of primary adrenal insufficiency during infancy or childhood and carried compound heterozygous STAR mutations (p.Gln258* and p.Arg188His, p.Gln258* and p.Met225Thr, and p.Gln258* and p.Arg272Cys). In all four patients, thelarche and menarche spontaneously occurred from 10 to 11 years of age and from 12 to 14 years of age, respectively. Subsequently, their menstruation cycles were regular at almost 1-month intervals. Patient 1 conceived naturally twice, and patient 2 conceived with the use of clomiphene citrate for ovulation induction. These two patients maintained the pregnancies without progesterone replacement therapy and successfully delivered children. CONCLUSION: Patients with nonclassic LCAH maintain ovarian function, which enables normal pubertal development and a successful pregnancy outcome without progesterone replacement therapy.

Transverse testicular ectopia associated with persistent Müllerian duct syndrome treated by transseptal orchiopexy: A case report.

RATIONALE: Persistent Müllerian duct syndrome (PMDS) is rare form of male pseudohermaphroditism characterized by the presence of uterus and fallopian tubes with normal external genitalia and secondary sexual characteristics. Transverse testicular ectopia (TTE) is also a rare form of testicular ectopia that may be associated with PMDS. PATIENT CONCERNS: We present a 2-year-old boy who presented with bilateral non-palpable testes with left inguinal mass. DIAGNOSIS: TTE with PMDS. INTERVENTIONS: On exploration, both testes were present in the left inguinal region. Uterus and fallopian tubes were located between the testes. A hysterectomy was perfomed with resection of the underdeveloped fallopian tubes. Bilateral orchiopexy was performed by placing both gonads into subdartos pouches in each scrotum with transseptal approach. OUTCOMES: Both testes were palpable in both the scrotum at 1-year postoperative follow-up and we are planning a regular follow-up. LESSONS: In case of TTE with PMDS, optimal surgical approach with orchiopexy and excision of Müllerian duct should be needed. A long-term postoperative follow-up is necessary for assessment of malignant transformation and infertility.

[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.

Prostatic adenocarcinoma in the setting of persistent müllerian duct syndrome: a case report.

Persistent müllerian duct syndrome (PMDS) is a form of disordered sex development in which rudimentary müllerian structures are identified in phenotypically and genotypically normal males. It is caused by defects in the anti-müllerian hormone (AMH) system. Since patients with PMDS present with undescended testes, testosterone production by Leydig cells later in life is often decreased. The role of androgens in prostate cancerogenesis is well known. Cryptorchid testes and diminished testosterone levels in post-pubertal life in patients with PMDS play a protective role against prostate cancer, and hence, prostate cancer is a rare event in patients with PMDS. Herein, we present a patient who underwent prostatectomy for high-grade prostatic adenocarcinoma with persistent müllerian structures (such as rudimentary uterus, fallopian tubes, and cervix) identified during surgery. To our knowledge, this is the second case reported in the English language literature where PMDS was associated with prostate cancer.

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.

Adrenarche unmasks compound heterozygous 3ß-hydroxysteroid dehydrogenase deficiency: c.244G>A (p.Ala82Thr) and the novel 931C>T (p.Gln311*) variant in a non-salt wasting, severely undervirilised 46XY.

3ß-Hydroxysteroid dehydrogenase type II deficiency (3ßHSD2) congenital adrenal hyperplasia is a rare cause of ambiguous genitalia, resulting in abnormal virilisation in both 46XY and 46XX. We describe a case of 46XY ambiguous genitalia that was misdiagnosed as androgen insensitivity syndrome. The correct diagnosis was made after adrenarche. Genotyping demonstrated compound heterozygosity in two alleles, the previously described c.244G>A (p.Ala82Thr), and a novel 931C>T(p.Gln311*) variant. We suggest that adrenarche unmasked the condition by driving cortisol production to rates that caused the mutant 3bHSD2 enzyme to become rate limiting for cortisol production. This case illustrates how markedly different the effects of this condition may be on androgen production compared with glucocorticoid and mineralocorticoid production. It also demonstrates how current guidelines based on urinary steroids and cortisol sufficiency may not arrive at the correct diagnosis, and underlines the importance of gene testing in the work-up of disorders of sexual differentiation.

[Persistent mullerian duct syndrome : Rare incidental finding during treatment of pediatric inguinal hernia]. / Das persistierende Müller-Gang-Syndrom : Ein seltener Zufallsbefund bei der Versorgung kindlicher Leistenhernien.

BACKGROUND: Persistent mullerian duct syndrome (PMDS) is a rare, autosomal recessive disorder. It is a form of male disorder of sexual differentiation in which mullerian duct structures are present in male phenotypes and 46XY karyotypes. In affected individuals, uterus, fallopian tubes, cervix and vagina are present. METHODS: A 2-month-old boy was admitted to hospital with a right-sided inguinal hernia. The physical examination showed a phenotypically normal boy with a right sided indirect inguinal hernia and impalpable testis. During herniotomy, a uterus and two fallopian tubes were found in the pelvic peritoneum adjacent to the two gonads. Initial biopsies were taken from the gonads and blood was sent for karyotyping. RESULTS: The biopsy showed normal testicular tissue without any ovarian tissue and the karyotyping result was 46XY; therefore, the diagnosis of persistent mullerian duct syndrome (PMDS) was made. In a second laparoscopically assisted operation the uterus and fallopian tubes were dissected, an orchidopexy of the left testis and an orchiectomy of the right testis were performed. The postoperative course was uneventful. CONCLUSION: In the case of an incarcerated inguinal hernia in combination with impalpable testis, a PMDS should be considered as a differential diagnosis.

[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.