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The study shows that whole‐exome sequencing is a promising approach to detect novel variants—and gene candidates in DSD, that, as a future direction, may improve the diagnostic gene panels for this heterogeneous disorder., The study shows that whole‐exome sequencing is a promising approach to detect novel variants—and gene candidates in DSD, that, as a future direction, may improve the diagnostic gene panels for this heterogeneous disorder

Persistent Mullerian duct syndrome (PMDS) is usually an accidental finding either during orchidopexy or during routine inguinal hernia repair in male patients presenting with undescended testes. It is a rare form of internal male pseudohermaphroditism caused by defect in synthesis or action of Mullerian inhibiting factor due to which Mullerian derivatives such as uterus, fallopian tube and upper vagina are normally present in 46XY males. PMDS has an autosomal recessive inheritance. Screening of the siblings is necessary. Familiarity of operating surgeon with this disease condition would increase the chances of correctly diagnosing the case. Distinguishing PMDS from other intersex disorder is critical. A karyotyping and assessment of testicular response to chorionic gonadotropin stimulation are essential to verify both genetic sex and existence of functional testicular tissue. Here we report a 7 year old male presenting with bilateral undescended testes.

A pseudohermaphrodite represents a human being whose gonads are consistent with the chromosomal sex but who has external genitalia resembling the opposite sex. Male pseudohermaphrodites are characterized by normal testes with insufficient masculinization of the wolffian duct system and external genitalia. Patients with female pseudohermaphroditism have female internal genitalia and karyotype (XX) and various degree of external genitalia virilization. We present the case of a fetus with male pseudohermaphroditism, detected at 21 weeks of pregnancy during the second trimester morphology exam, with no other anomalies present. The peculiarity of this case is represented by the fact that the initial supposition was of clitoral hypertrophy (female pseudohermaphroditism), but after amniocentesis incomplete masculinization causes are being explored (male pseudohermaphroditism).

Orientador: Maricilda Palandi de Mello Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: Para um correto desenvolvimento sexual masculino em humanos, é necessária a presença, entre outros, de dois hormônios esteróides: a testosterona (T) e a diidrotestosterona (DHT). A T é o hormônio responsável pelo desenvolvimento da genitália interna masculina, já a DHT é o hormônio chave da virilização da genitália externa masculina e responsável pelo estabelecimento dos caracteres sexuais secundários durante a puberdade. Duas enzimas são responsáveis pela produção destes hormônios: a enzima 17?-hidroxiesteróide desidrogenase tipo 3 (gene HSD17B3), a qual é responsável pela conversão do hormônio androstenediona em T, reação realizada na última etapa da biossíntese da T e a enzima 5?-redutase tipo 2 (gene SRD5A2), que é responsável por catalisar a conversão da T em DHT. Mutações nos genes HSD17B3 ou SRD5A2 causam alterações que levam à não produção ou à síntese defeituosa das enzimas 17?-hidroxiesteróide desidrogenase tipo 3 e 5?-redutase tipo 2, promovendo deficiência na virilização de indivíduos 46,XY. Indivíduos estes cujas gônadas são representadas por testículos, apresentam pseudo-hermafroditismo masculino (PHM), agora denominado distúrbio da diferenciação do sexo em indivíduos 46,XY (DDS-XY). Estes podem apresentar genitália ambígua, sendo o sexo de criação predominantemente feminino, com virilização na puberdade. O diagnóstico pode ser confirmado com a identificação de mutações nos genes específicos HSD17B3 e SRD5A2. Assim, o objetivo desse estudo foi investigar alterações moleculares nos genes HSD17B3 e SRD5A2, em pacientes com ambiguidade genital com cariótipo 46,XY, e contribuir para a confirmação do diagnóstico clínico e laboratorial de DDS em indivíduos 46,XY por deficiências nas enzimas 17?-hidroxiesteróide desidrogenase tipo 3 e 5?-redutase tipo 2. A metodologia empregada neste estudo teve por base a amplificação dos 11 exons do gene HSD17B3 e dos 5 exons do gene SRD5A2 pela reação em cadeia da polimerase (PCR), seguida por rastreamento das mutações através do sequenciamento direto dos produtos de amplificação. Das 2 famílias estudadas para diagnóstico de alterações no gene HSD17B, foi encontrada uma alteração, p.R80Q, em homozigose em um paciente. E para o para o gene SRD5A2, foram estudadas 45 famílias, e foi verificada a presença de três mutações: a c.418delT em homozigose em um paciente, a c.278delG em heterozigose em um paciente e a p.Q126R em homozigose em duas irmãs. Vários polimorfismos freqüentes foram observados e, também, algumas riações nucleotídicas novas ou raras foram identificadas. Fez parte do estudo a avaliação in vitro da mutação g.49529G>A, já descrita previamente como uma mutação missense (p.G183S), quanto ao efeito deletério no processo de splicing, uma vez que esta alteração encontra-se no último nucleotídeo do exon 3 do gene SRD5A2. Foi verificado que esta alteração promove a excisão do exon 3, mostrando que o efeito primário desta mutação não é a troca de aminoácidos e sim uma alteração no processo de splicing deste gene. Abstract: The male sexual development requires the production of normal amounts of two steroid hormones: testosterone (T) and dihydrotestosterone (DHT). The T is responsible for development of male internal genitalia, whereas DHT is the key for the virilization of the male external genitalia and responsible for the establishment of secondary sexual characteristics during puberty. Two enzymes are responsible for the production of these hormones: 17?-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3 gene), which is responsible for converting androstenedione to T, the last step of the biosynthesis of T; and 5?-reductase type 2 enzyme (SRD5A2 gene), which is responsible for catalyzing the conversion of T into DHT. Individuals with 46,XY karyotype and mutations in either HSD17B3 gene or SRD5A2 gene, present a deficiency of enzyme activity that leads to phenotypes ranging from male with ambiguous genitalia to normal female. Such individuals may be assigned at birth and raised as females. The gonads of those individuals are represented by testes. This condition defines the male-pseudohermaphroditism (MPH), recently renamed as disorder of sexual development in 46,XY karyotype (DSD-XY). The diagnosis of these deficiencies can be confirmed with the identification of mutations in either HSD17B3 or SRD5A2 genes. The aim of this investigation was to identify nucleotide alterations in the HSD17B3 gene or in the SRD5A2 gene in patients with clinical and hormonal characteristics suggestive of 17?-hydroxysteroid dehydrogenase type 3 deficiency, or 5?-redutase type 2 deficiency. Molecular analysis was performed by amplification of the eleven exons of HSD17B3 gene, and the five exons of SRD5A2 gene followed by sequencing. In two families studied for the HSD17B3 gene, one alteration was detect, p.R80Q, in a homozygous patient. Forty-five families were studied for SRD5A2 gene and the presence of three mutations was verified: the c.418delT in one homozygous patient, the heterozygosis for c.278delG in one patient and the homozygosis for p.Q126R in two sisters. Several frequent polymorphisms in the SRD5A2 gene were observed and some novel or rare variations were identified as well. The study in vitro with the g.49529G>A mutation was also performed due to the possibility of deleterious effect on the splicing process, although his mutation had been previously described as a missense mutation (p.G183S). It was verified exon 3 skipping in the mRNA as a result of the mutation, showing that the primary effect is not the change of amino acids but the anomalous splicing process of the SRD5A2 gene. Mestrado Genética Animal e Evolução Mestre em Genética e Biologia Molecular

Background : Hermaphroditism is a rare congenital disease that causes ambiguous sexual features. True hermaphrodites have testicular and ovarian tissue, whereas pseudohermaphrodites have only one type of gonadal tissue, genitalia, but secondary characteristics of the opposite sex. Pseudohermaphrodites are classified as male or female according to their gonads. Treatment of pseudohermaphroditism consists of surgical removal of the gonads including reconstruction of abnormal genitalia, especially if the urethra is involved. Therefore, the objective of this report is to describe a case of a male pseudohermaphrodite in a dog treated with clitoridectomy with urethrostomy. Case : A 7-month-old, mixed-breed dog was referred due to the presence of a flaccid structure similar to a small penis, containing an os clitoris , bulbourethral glands, and urethra protruding from the vulva. Physical examination, complete blood count and serum biochemistry were within normal ranges. Hormonal levels of estradiol, testosterone, and progesterone were 56.39 pg/mL, 127.9 ng/mL, and 0.892 ng/mL, respectively. The abdominal ultrasound and posteriorly the exploratory celiotomy found a normal size prostate and two round organs resembling testicles connected to a uterus-like tubular structure. The patient underwent surgical abdominal exploration that confirmed the ultrasonographic findings and led to gonadohysterectomy. Also, clitoridectomy and urethrostomy were performed to excise the protruded structure and maintain normal urethral patency. The histopathological examination of the clitoris and penis confirmed it was a male genital organ, however, the abdominal structures were compatible with the testicles, epididymis, uterus, and even a broad ligament. These organs are normally found in cases of male pseudohermaphroditism. The testicles were histologically composed of regular seminiferous tubules, single layer Sertoli cells but there were no spermatogenic cells. After ten months of follow-up, the patient was alive, without urination impairment or any other clinical signs. Discussion : The animal presented the protrusion of the penile structure as the sole clinical sign. The reproductive system had a female origin, been possible its masculinization due to high testosterone concentration that induced the development of Wolff ducts, resulting in the formation of the epididymis, deferent ducts, and seminal vesicles. In these cases, it led to an enlarged clitoris. The patient described had hormonal levels compatible with a neutered male/female or a female in anestrus. The clinical signs become evident as the clitoris gets hypertrophied increasing the sensibility, resulting in constant licking of the mucosa, chronic inflammation, and mucopurulent discharge. This patient was diagnosed with male pseudohermaphroditism as it had cryptorchid male gonads along with the uterus and external genitalia of a female dog but containing traces of male genitals such as the os clitoris . Surgery is indicated when there are clinical signs or when the clitoris had an os clitoris or urethra due to an intersex abnormality. The surgical resection of the external male genitalia associated with the excision of the internal reproductive tract treated while preserving the urethra in this animal. Clitorectomy is a simple technique and creates a normal female anatomy ending the clinical signs of the exposed clitoris and improving the quality of life. Clitoridectomy and Urethrostomy in a Pseudohermaphrodite Dog

This case study highlights that how a disorder of sexual development when goes unnoticed at birth and unreported during childhood or adolescence can present with major problems and even complications in adulthood. Since our patient was young and in a childbearing age, he presented with bilateral undescended testes and orgasmic anejaculation when he first came to the hospital. Subsequently, having a normal 46XY karyotype but remnants of persistent Mullerian duct made him little confused about his identity. After giving him the confidence, that he was still a male and could lead the life he did previously, the explanation about future risk of malignancy in the intra-abdominal testes was another difficult task. Early detection and management of male pseudohermaphroditism with persistent Mullerian duct requires a co-ordinated approach of a team of endocrinologist, physician, surgeon and radiologist. Integrated imaging in the form of ultrasound, genitography and MRI is important in demonstrating the anatomy, classification, possible effects or congenital malformations in other organs, warning patients of any risk of neoplasia and guiding the clinician to plan other investigations, hormonal replacement or reconstruction surgery if required. Such a systemic approach that allays anxiety and gives psychological relief to the patient should be taken as it can deeply change the life of a person and their family.

Persistent Mullerian duct syndrome has been described as a disease of internal male pseudohermaphroditism, a rare autosomal recessive disease, characterised by persistent Mullerian derivatives in patients with male pattern 46, XY karyotype and normal pattern virilisation. We present a case of an elderly man, who on evaluation for bilateral undescended testes was found to have a pelvic mass suggestive of malignant transformation of an undescended testis on imaging. On surgical exploration, uterus with multiple fibroids, bilateral fallopian tubes, cervix and bilateral atrophic testes were identified. Interestingly, in this case, imaging (contrastCT and MRI) had missed Mullerian structures due to varied presentation, but exploration and excision of the structures followed by their histopathology revealed uterine leiomyomas and confirmed other Mullerian structures (bilateral fallopian tubes, cervix) with bilateral testes.

Introduction: Persistent Mullerian duct syndrome (PMDS) is a scarce type of male pseudohermaphroditism due to anti-Mullerian hormone dysfunction. So, Mullerian duct derivatives such as the uterus, cervix, fallopian tubes, and two-thirds of the vagina are seen in a normal phenotypic and genotypic male. Considering and assessing the clinical manifestations, associated diseases, histopathology, and imaging findings can be clues in the management of such cases. Case Presentation: Here, we describe a case of PMDS with left inguinal hernia and bilateral cryptorchidism and discuss the management and review of the literature. Also, the case has a history of brain mass with a pathologic diagnosis of ganglioneuroma. Is there a correlation between PMDS and extragenital neoplasm? it needs more investigation in the future. Conclusions: Bilateral cryptorchidism could provide us with a hint toward PMDS diagnosis. However, genetic counseling will be required, particularly in parental consanguinity.

Introduction: Persistent Mullerian duct syndrome is a rare disorder of male organ development characterized by internal male pseudohermaphroditism. Persistent Mullerian duct syndrome is usually an incidental finding in patients presenting cryptorchidism, inguinal hernia, or a previous story of undescended testes. Case description: We report on two cases of persistent Mullerian duct syndrome: an adult fertile male with uterus and ectopic prostate occurring as pelvic mass and a 75-year-old organ donor with uterus and two fallopian tubes, discovered in course of organ recruitment. We performed routine histological analysis and immunohistochemical profiling of the different tissue components. Examined tissues were all benign, and the living patient is well after surgery. Conclusion: In order to prevent further complications such as infertility and potential malignant change, surgeons and surgical pathologists must be aware of this condition and should consider excision of the Mullerian remnant where possible.

Persistent Mullerian duct syndrome (PMDS) is usually an accidental finding either during orchidopexy or during routine inguinal hernia repair in male patients presenting with undescended testes. It is a rare form of internal male pseudohermaphroditism caused by defect in synthesis or action of Mullerian inhibiting factor due to which Mullerian derivatives such as uterus, fallopian tube and upper vagina are normally present in 46XY males. Here we present a case report of a 7 year old male presenting with bilateral undescended testes.

Background 17α-hydroxylase deficiency is a rare autosomal recessive disorder caused by mutations in the cytochrome P450 family 17 subfamily A member 1 gene. The major clinical presentation includes hypertension, hypokalemia, male pseudohermaphroditism and female gonadal dysplasia. Hundreds of pathogenic variants have been reported in this disorder, and some common mutations were found to be race-specific. Case presentation In this study, we reported 5 Chinese girls with 17α-hydroxylase deficiency from Henan Province. The patients all came to the hospital for hypertension, and they also presented with sexual infantilism. The average age of the patients was 14 years old, ranging from 12 to 17 years old. They all had reduced blood cortisol, estradiol (E2), and testosterone (TESTO) and increased adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). They all had the appearance of females; however, three of the chromosome karyotypes were 46XX, and two were 46XY. Conclusions All of the patients carried a mutation on the 329 amino acid of CYP17A1 exon 6. By summarizing the currently known pathogenic mutations of 17α-hydroxylase deficiency, we demonstrated the prevalence of these gene mutations in Chinese Han and non-Chinese populations.

Hydroxysteroid (17β) dehydrogenase type 3 (HSD17B3) deficiency causes a disorder of sex development in humans, where affected males are born with female-appearing external genitalia, but are virilized during puberty. The hormonal disturbances observed in the Hsd17b3 knockout mice (HSD17B3KO), generated in the present study, mimic those found in patients with HSD17B3 mutations. Identical to affected humans, serum T in the adult HSD17B3KO mice was within the normal range, while a striking increase was detected in serum A-dione concentration. This resulted in a marked reduction of the serum T/A-dione ratio, a diagnostic hallmark for the patients with HSD17B3 deficiency. However, unlike humans, male HSD17B3KO mice were born with normally virilized phenotype, but presenting with delayed puberty. In contrast to the current belief, data from HSD17B3KO mice show that the circulating T largely originates from the testes, indicating a strong compensatory mechanism in the absence of HSD17B3. The lack of testicular malignancies in HSD17B3KO mice supports the view that testis tumors in human patients are due to associated cryptorchidism. The HSD17B3KO mice presented also with impaired Leydig cell maturation and signs of undermasculinization in adulthood. The identical hormonal disturbances between HSD17B3 deficient knockout mice and human patients make the current mouse model valuable for understanding the mechanism of the patient phenotypes, as well as endocrinopathies and compensatory steroidogenic mechanisms in HSD17B3 deficiency.

There are four types of intersex disorders: female pseudohermaphroditism (genetic female with masculinized phenotype), male pseudohermaphroditism (genetic male with feminized phenotype), true hermaphroditism, and gonadal dysgenesis. The most common intersex disorder is congenital adrenal hyperplasia. Treatments for intersex disorders depend upon the type of the disorder and the severity of the disease. Hypospadias is a developmental anomaly of the penis associated with ventral curvature of the shaft, a ventral opening of the urethral meatus, and abnormal distribution of the foreskin. Treatment is reconstructive surgery. Cryptorchidism is failure of one or both testes to descend into the scrotum. Undescended testicles are associated with increased risks of infertility and cancer. Treatment is surgical placement of the affected testicle into the scrotum or hormonal therapy to induce testicular descent. Other congenital scrotal abnormalities include inguinal hernia and hydrocele.

Highlights • Herniotomy and bilateral orchidopexy is recommended for TTE-PMDS. • No reports suggest malignancy from the mullerian structures. • Division of mullerian structures is done only if it interferes with orchidopexy. • Malignancy may arise in the testis though histologically normal., Introduction Persistent Mullerian duct syndrome (PMDS) is a rare type of male pseudohermaphroditism. Transverse testicular ectopia (TTE) is characterized by one testis moving to the opposite side and both testes traversing the same inguinal canal. Case presentation An 11-month-old boy presented with bilateral cryptorchidism. The left testis was not palpable; the right testis was canalicular with a right inguinal hernia. Ultrasound showed both testes located in the right inguinal canal. Right inguinal exploration revealed two testes with intact spermatic cords. A primitive uterus with fallopian tubes was also identified on opening the processus vaginalis. After herniotomy, bilateral orchidopexy was carried out (left orchidopexy through a trans-septal approach). Karyotyping confirmed a male gender (46XY). One year after the operation, ultrasound showed both testes to be in good condition. Discussion PMDS is caused by defects in the gene that encodes Antimullerian hormone(AMH). Treatment aims to correct cryptorchidism and ensure appropriate scrotal placement of the testes. Malignant transformation is as likely as the presence of abdominal testes in an otherwise normal man. Failing early surgical correction, gonadectomy must be offered to prevent malignancy. Division of the persistent mullerian duct structures is indicated only in patients where persistence interferes with orchidopexy. Conclusion TTE should be suspected in patients presenting with inguinal hernia on one side and cryptorchidism on the other side. Herniotomy and bilateral orchidopexy is optimal. Removal of mullerian structures may injure the artery to vas deferens and is hence not recommended. Follow-up for fertility assessment in the latter years should be counselled.

17β-hydroxysteroid dehydrogenase 3 deficiency consists of a defect in the last phase of steroidogenesis, in which androstenedione is converted into testosterone and estrone into estradiol. External genitalia range from female-like to atypical genitalia and most affected males are raised as females. Virilization in subjects with 17β-HSD3 deficiency occurs at the time of puberty and several of them change to male social sex. In male social sex patients, testes can be safely maintained, as long as they are positioned inside the scrotum The phenotype of 46,XY DSD due to 17β-HSD3 deficiency is extremely variable and clinically indistinguishable from other causes of 46,XY DSD such as partial androgen insensitivity syndrome and 5α-reductase 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio due to high serum levels of androstenedione and low levels of testosterone. The disorder is caused by a homozygous or compound heterozygous mutations in the HSD17B3 gene that encodes the 17β-HSD3 isoenzyme leading to an impairment of the conversion of 17-keto into 17-hydroxysteroids. Molecular genetic testing confirms the diagnosis and provides the orientation for genetic counseling. Our proposal in this article is to review the previously reported cases of 17β-HSD3 deficiency adding our own cases.

Androgen insensitivity (testicular feminization) syndrome is a rare inherited form of male pseudohermaphroditism that occurs in a phenotypically normal woman with male karyotype (XY). We present a case of a 20 years old patient who had history of primary amenorrhea. The clinical examination shows a female phenotype: the breasts are normally developed, absence of hair in the groins and axillary areas, short blind vagina, absent cervix and uterus. A firm mass measuring 5x3 cms was palpable in the left inguinal region. MRI pelvis revealed a cystic lesion measuring 6.8x5.5 cms on the right side. Histopathological examination revealed that both the masses were composed of testicular tissue with absence of ovarian component. The testes were removed to avoid the risk of malignancy. The patient was counseled and discharged with lifelong hormone replacement therapy.

We are reporting a case of an 18-month old male who presented with bilateral cryptorchidism. The patient underwent an explorative laparoscopy in which two gonads were identified in close proximity to the uterus and fallopian tubes. Biopsy of the gonads confirmed testicular tissue. Genetic analysis demonstrated a 46, XY male. Male external genitalia were appropriate for age with no evidence of female structures. Persistent Mullerian duct syndrome is extremely rare, with approximately 260 cases reported in the literature. Best practice for the extent of surgical management is still evolving as we gather data on long-term outcome Keywords: cryptorchidism, Mullerian duct syndrome, male pseudohermaphroditism, undescended testicle

Persistent Mullerian duct syndrome (PMDS) is a rare form of male pseudohermaphroditism; it is defined by the presence of the Mullerian duct derivatives (the uterus, the fallopian tubes, and the upper vagina) in genotypically and phenotypically males. Seminoma is the most common type of testicular tumor in the third and fourth decade of life. We report a case of intra-abdominal seminoma in a patient with bilateral undescended testes and persistent Mullerian duct syndrome.

Two American Cocker Spaniels and one Bichon Frise were presented to our veterinary teaching hospital with an enlarged clitoris. Diagnostic imaging showed that the structure was composed of bony material. Exploratory laparotomy revealed uterine-like structures and testes which had an epididymis unilaterally. Surgical removal of internal genitalia, gonads and protruded clitoris were performed well. Histological evaluation revealed; inactive testes, female internal genital tracts with ambisexual ductal remnants, and prominent ossification in the clitoris. All 3 cases were diagnosed with male pseudohermaphroditism. In author's knowledge, this is the first report in Bichon Frise dog with os clitoris and also, it describes not common cases in small dog breeds with os clitoris.

Introduction Persistent Mullerian duct syndrome (PMDS) is an autosomal recessive disorder characterized by the persistence of Mullerian duct derivatives (uterus, cervix, fallopian tubes and proximal vagina) in a phenotypically and karyotypically male patient. This internal male pseudohermaphroditism is usually an incidental diagnosis in children who present with cryptorchidism and inguinal hernia or in adults with cryptorchidism, infertility or an abdominal mass. PMDS is associated with a higher risk of malignant transformation of gonads. Here we present a case of testicular seminoma in an adult infertile patient with persistent MDS. The patient had laparoscopic bilateral orchidectomy with removal of fallopian tubes and commenced on long-term testosterone supplement therapy. Subjects and materials A 42 years old morbidly obese (body mass index 57) infertile male patient had an elective admission for bariatric surgery. During pre-operative assessment, he was investigated for infertility and had an inguinoscrotal ultrasound to locate undescended testes. Postoperatively, he had MRI abdomen and pelvis. Six months later he had an urgent contrast enhanced CT abdomen and pelvis to rule out the causes of his right flank pain. Result Pre-operative inguinoscrotal ultrasound revealed no testicular tissue in either the inguinal canals or the scrotum [figure 1]. Genetic screening confirmed 46 XY Karyotyping and hormonal profile showed raised FSH (26.3 IU/L) and LH (14.2 IU/L) and normal testosterone level (11.3 ng/ml). MRI pelvis confirmed the presence of a small, rudimentary uterus and bilateral fallopian tubes and identified bilateral adnexal masses (gonads) measuring about 3×2 cm. Emergency contrast enhanced CT abdomen [figure 1] showed a complex heterogeneous mass containing some air foci in right iliac fossa with twisted engorged vascular pedicle unrelated to bowel loops, presumed to be a twisted gonad. Following imaging evaluation, patient underwent laparoscopic removal of this mass, mildly congested appendix, normal looking left gonad and both fallopian tubes. Rudimentary uterus was left behind undisturbed. Histopathological analysis confirmed these gonads to be testicles with marked atrophic changes. Right sided testicle showed haemorrhagic infarction consistent with torsion along with a 5.5 cm classic seminoma [figure 1]. Full circumference fallopian tube and fimbria were identified bilaterally. Because of bilateral orchidectomy with normal male karyotype and normal male secondary sexual characters, regular testosterone hormone replacement therapy (testosterone 1000 mg/every 3 month) was instituted. Conclusion Patients with persistent Mullerian duct syndrome or internal male pseudohermaphroditism have 46 XY karyotype, near normal development of secondary sexual characters and persistent Mullerian duct structures i.e., uterus, cervix, fallopian tubes and proximal vagina. Our patient was diagnosed very late possibly due to cultural issues and stigmata attached to pseudohermaphroditism.

Persistent Mullerian Duct Syndrome (PMDS) is a rare form of male pseudohermaphroditism characterized by the presence of Mullerian duct structures in an otherwise phenotypically and genotypically normal male. We present the case of a 30-year-old male patient with high levels of serum beta human chorionic gonadotrophin (β-HCG) who was subjected to exploration with a preoperative presumptive diagnosis of a tumour in undescended, abdominal testes made on the basis of a detailed history, clinical and radiological examination (USG & CT Abdomen). On exploration, bilateral testicular tumour masses (subsequently proven to be seminomas on histopathology) and an unrecognizable pelvic structure (subsequently proven to be a uterus on histopathology) were removed. The patient refused chemotherapy and was followed up further for six months without any evidence of disease recurrence.

Normal male development requires three conditions: (1) adequate differentiation of the fetal testis; (2) synthesis and secretion of testicular hormones; and (3) effective action of these hormones on target organs. This requires the combined action of the inhibitory anti-müllerian hormone (AMH, secreted by Sertoli cells) to block the development of the uterus and fallopian tubes from the müllerian duct, together with the trophic stimulus of testosterone (a Leydig cell product), which leads to virilization of the wolffian ducts. Additionally, the development of external genitalia depends on the conversion of testosterone to dihydrotestosterone by the enzyme 5-α-reductase. Failure of any of these mechanisms leads to deficient virilization or the so-called "male pseudohermaphroditism" syndromes.

Frasier syndrome is a rare inherited disease characterized by steroid-resistant nephrotic syndrome, gonadal tumor, and male pseudohermaphroditism (female external genitalia with sex chromosomes XY), which is based on a splice site mutation of Wilms tumor-suppressor gene 1 (WT1). Several unusual Frasier syndrome cases have been reported in which male pseudohermaphroditism was absent. We reviewed 88 Frasier syndrome cases in the literature and classified them into three types (type 1–3) according to external genitalia and sex chromosomes, and described their clinical phenotypes. Type 1 Frasier syndrome is characterized by female external genitalia with 46,XY (n = 72); type 2 by male external genitalia with 46,XY (n = 8); and type 3 by female external genitalia with 46,XX (n = 8). Clinical course differs markedly among the types. Although type 1 is noticed at the mean age of 16 due to mainly primary amenorrhea, type 2 and 3 do not present delayed secondary sex characteristics, making diagnosis difficult. The prevalence of gonadal tumor is high in type 1 (67%) and also found in 3 of the 8 type 2 cases, but not in any type 3 cases, which emphasize that preventive gonadectomy is unnecessary in type 3. On the basis of our findings, we propose a new diagnostic algorithm for Frasier syndrome. Cancer Prev Res; 8(4); 271–6. ©2015 AACR.

According to additional anomalies, transverse testicular ectopia (TTE) is classified into three groups. Type-2 TTE, accompanied by persistent mullerian duct syndrome, constitutes approximately 20% of the patients. Surgical treatment should be planned after careful physical examination, ultrasonography, and genetic/endocrinologic evaluation. Herniorrhaphy, orchiopexy with testicular biopsy, and excision of the mullerian structures are the most appropriate surgical approaches in cases of TTE with persistent mullerian duct syndrome. We aimed to share our approach to the diagnosis and treatment of a patient with type-2 TTE. Possibility of TTE should be kept in mind in children with nonpalpable testis on one side and inguinal hernia on the other side.

Disorders of sex development (DSD) are congenital diseases in which the chromosomal, gonadal, or anatomical sex is abnormal and embraces a wide-ranging spectrum of phenotypes classified in five different groups ( Hughes et al., 2006 ). The first class involves disorders of gonadal differentiation; the second comprehends ovotesticular DSD (formerly known as true hermaphroditism); the third includes 46,XX DSD (formerly known as female pseudohermaphroditism); the fourth encloses 46,XY DSD (formerly known as male pseudohermaphroditism); and the fifth group consists of unclassified forms. When such a child is born, both the parents and a multidisciplinary medical staff are opposed to demanding decisions regarding gender assignment, genital surgery, and fertility issues. In this article, only conditions where testes are involved is going to be addressed.

The current report aimed to characterize plasma anti-Mullerian hormone (AMH) in bovine male pseudohermaphroditism. The blood AMH concentration in a Japanese Black male pseudohermaphrodite calf was compared with pre- and post-pubertal male and female calves and castrated calves. The concentration in the case was higher than in post-pubertal males, castrated males, and pre- and post-pubertal female calves (p

Persistent Müllerian duct syndrome (PMDS) is a rare type of male pseudohermaphroditism caused by a deficiency in anti-Müllerian hormone (AMH) or a defect in its type II receptor. The current study reports the clinical data and results of the genetic analysis of a 17-month-old male diagnosed with PMDS. The clinical manifestations of the patient included a left transverse testicular ectopia and bilateral cryptorchidism. Pelvic ultrasonography indicated two testes on the same left inguinal ring and left inguinal hernia and uterine tissue located at the left rear of the bladder. Karyotype analysis detected a 46,XY chromosome pattern and tests determined that the level of AMH was increased. Gene sequencing of AMHR-II indicated a compound heterozygous nucleotide variation and identified two novel mutations. The c.1184 (E9) to c.1185 (E9) CT deletion mutant gene originated from the father of the patient. This mutation causes a frameshift resulting in a truncated protein. The c.1388G>A (E10) mutant site was derived from the patient's mother and caused a change in p.463, R>H, resulting in the alteration of the structure of the protein, which subsequently induced a conformational change in AMHR-II. The results of the current study may help to further understanding of the PMDS genetic profile.

Male pseudohermaphroditism is not commonly reported in veterinary medicine. Here, a 3-year-old Maltese/poodle mixed dog presented with malformed external genitalia and episodic hematuria. Inspection and palpation of the external genitals showed a malformed penis, shortened prepuce, external urethral orifice, and cryptorchidism. There was no urethral meatus at the tip of the penis. The urethral opening was situated between the prepuce and the penis. The anterior half of the prepuce was absent, and the penis was free and exposed to both trauma and licking. Plain radiographic examination showed absence of an os penis in the penis. A double-contrast cystograph showed the suspected uterus as well as the cystic calculi. A hypoechoic space was seen at the dorsal portion of the urinary bladder. The space was suspected to be the uterus. A sagital ultrasonograph showed cystic calculi in the urinary bladder. During surgery to remove cystic calculi, hypoplastic testes as well as the uterus were observed. Histological examination of the testes showed the seminiferous tubules and interstitial cells. The sertoli cells and spermatogonia were adjacent to the basement membrane. No evidence of spermatogenesis was found. Striated squamous epithelial cells and smooth muscle cells were found in the uterus. This dog had vestigial oviducts as well as a uterus with male-appearing external genitals.

La feminización testicular es una afección genética recesiva ligada al cromosoma X, con insensibilidad andrógenica completa, siendo la variedad más frecuente de pseudohermafroditismo masculino. La producción de andrógenos por los testículos es normal, pero no hay acción por ausencia de receptores en los órganos diana. Los individuos 46,XY muestran ambos testículos, genitales externos femeninos, vagina con extremo ciego y ningún derivado miileriano. La incidencia es alrededor de 2 a 5 por 100,000, el fenotipo es femenino. Se presenta un caso atendido en el Instituto Materno Perinatal en el año 2003, en quien el estudio y manejo fue por varias especialidades.

A Pit-bull and a Beagle, both one-year-old, with complaints of an enlarged clitoris were clinically suspected for hermaphroditism. The enlarged clitoris, the uteri and the gonads were removed surgically from each animal and submitted to our department for histopathological evaluation. Tissue samples were fixed with 10% buffered formalin solution and processed routinely, after which paraffin sections were obtained and stained with H&E. A blood sample was taken from the Beagle dog and a peripheral lymphocyte culture was prepared. While the clitoris and uteri were confirmed histopathologically, the gonads were detected as a testis instead of an ovary for both dogs. Additionally, cytogenetic evaluation revealed a normal female chromosome complement, 78, XX for the Beagle dog. According to the gonadal and phenotypic sexes, both cases were first determined as 'male pseudohermaphroditism', a phenotypic sex disorder. However , after karyotyping analysis, we concluded that the 78, XX Beagle dog should be defined as suffering from XX sex reversal syndrome, a gonadal sex disorder.

Testicular feminization syndrome or androgen insensitivity syndrome is a rare inherited form of male pseudohermaphroditism that occurs in phenotypically normal woman with male karyotype (XY), with an incidence of 1:20,000-64,000 male births. The individual with complete form of this syndrome have female external genitalia while those with partial form have variable ambiguity of genitalia. The undescended testis may go into malignant transformation. The androgen insensitivity syndrome with malignant testicular disorder is very rare. A twenty-eight year old female was admitted to the hospital with the complaint of primary amenorrhea. Clinical and laboratory investigation revealed testicular feminization syndrome with seminoma developed from intraabdominal undescended testis. Primary removal of the mass and postoperative chemotherapy was treatment of choice for the patient.

Streak gonads with epithelial cords have a great morphological similarity to the first recognizable passage of a gonad that has initiated a development toward the testicle. Most of these gonads still retain an elongated shape, and the development of the seminiferous cords is very precarious. Streak gonads with epithelial cords is the characteristic gonad of incomplete (partial) 46,XY gonadal dysgenesis, the most common form of 46,XY gonadal dysgenesis. This is a very interesting group of DSD due to several reasons: the etiology is unknown in more than half of the cases, the high frequency with which germ cell tumors develop, and the association with different extragonadal manifestations such as campomelic dysplasia and renal disorder; myotonic dystrophy plus renal disease; progressive renal insufficiency (Frasier syndrome); associated renal insufficiency and Wilms tumor (Denys-Drash syndrome); mental retardation with or without facial anomalies and with or without short height; cleft palate, micrognathia, kyphoscoliosis, and clubfoot (Gardner-Silengo-Wachtel syndrome or genito-palato-cardiac syndrome); pterygium multiple syndrome; Graves’ disease; congenital universal alopecia, microcephalia, cutis marmorata, and short height; and peripheral neuropathy among others. The most common syndromes are reviewed in this chapter.

Dysgenetic testis is the characteristic gonad of genetically and phenotypically male patients with a defect in the anti-Mullerian hormone (AMH) system. There are three syndromes with persistent Mullerian derivatives: mixed gonadal dysgenesis, also known as asymmetrical gonadal differentiation or Sohval’s syndrome, dysgenetic male pseudohermaphroditism, and persistent Mullerian duct syndrome (PMDS), known as hernia uteri inguinalis or male with uterus. Although the predominant phenotype is masculine and consists of patients who consult for cryptorchidism and inguinal hernia, or infertility and azoospermia, there are also patients with female phenotype, short height, and with or without Turner’s syndrome. It is a group of DSD whose treatment is of significant complexity as to which action is to be taken with the gonads (orchiectomy versus descent), removal or not of Mullerian derivatives, and the need for close monitoring as it is a group of patients with a high tumor risk. Patients develop tumors not only in the dysgenetic testis but also in Mullerian remnants.

Dihydrotestosterone is a potent androgen metabolite formed from testosterone by action of 5α-reductase isoenzymes. Mutations in the type 2 isoenzyme cause a disorder of 46,XY sex development, termed 5α-reductase type 2 deficiency and that was described forty years ago. Many mutations in the encoding gene have been reported in different ethnic groups. In affected 46,XY individuals, female external genitalia are common, but Mullerian ducts regress, and the internal urogenital tract is male. Most affected males are raised as females, but virilization occurs at puberty, and male social sex develops thereafter with high frequency. Fertility can be achieved in some affected males with assisted reproduction techniques, and adults with male social sex report a more satisfactory sex life and quality of life as compared to affected individuals with female social sex.

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed almost exclusively in the testes and specifically converts the weak androgenic androstenedione to active testosterone (T) in the presence of NADPH. Additionally, studies have demonstrated that 17β-HSD3 is over-expressed in hormone-dependent prostate cancer. T, which interacts with the androgen receptor (AR), eventually stimulates the growth of prostate cancer cells. Defects in T synthesis or action impair the development of the male phenotype during embryogenesis and cause the autosomal recessive disorder male pseudohermaphroditism. Affected individuals are often born with female-appearing external genitalia and are reared as females. Since 17β-HSD3 plays a central role in T production, it has been recognized as a promising therapeutic target to reduce the circulating level of androgens and to suppress androgen-sensitive tumor proliferation. In recent decades, improvements have been made in the development of 17β-HSD3 inhibitors. Herein, we give an overview of the main structure and function of human 17β-HSD3 and summarize steroidal and non-steroidal inhibitors of 17β-HSD3, which can be a potential target for prostate cancer.

The Detection of the Complete Androgen Insensitivity Syndrome is not simple since diagnostic can start from different points, depending on clinical features. Four cases of complete androgen insensitivity syndrome are presented through diagnostic modalities and therapeutic approaches. The initial reasons for investigation were as follows: prenatal amniocentesis being in conflict with the postnatal phenotype, secondary clinical finding, testicle finding during hernia repair, and post pubertal primary amenorrhea. Complete chromosomal, hormonal and ultrasonographical investigations were performed in all patients. Laparoscopy or open inguinal approaches were performed for gonadectomy in all patients, and the microscopic finding was testicular tissue without malignancy. Complete Androgen Insensitivity Syndrome is a type of male pseudohermaphroditism that could be diagnosed as early as in pre-adult age, before any malignant changes appear, and early enough to reach the correct therapy in time.

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. Orv. Hetil., 2012, 153, 303–307.

Introduction: Androgen insensitivity syndrome is a form of malepseudohermaphrodite where the phenotype female has malegonads and is genotypically male.Case report: We report a case of complete androgeninsensitivity syndrome in a 22-year-old who underwentlaparoscopic gonadectomy.Discussion: Androgen insensitivity syndrome is the mostcommon cause of male pseudohermaphroditism and third mostcommon cause of primary amenorrhea.Conclusion: Laparoscopy is an effective method in androgeninsensitivity syndrome treatment, mainly due to the increasedrisk of malignant transformation of the testes. Psychosexualneeds should be addressed along with low-dose hormonaltherapy to maximize long-term success.

Summary This report describes the surgical anatomy and successful removal of the internal gonads in a 6-year-old male pseudohermaphrodite Friesian horse by standing laparoscopy. Gonads could not be identified by physical or ultrasonographic examination and bilateral standing flank laparoscopy revealed the presence of intra-abdominal gonads suspended from the dorsal aspect of the abdominal cavity by 10–15 cm long vascular pedicles. No evidence of female internal genitalia such as a uterus was found and bilateral gonadectomy was performed laparoscopically. Histological analysis of the excised gonads confirmed the diagnosis of male pseudohermaphroditism. Minor cosmetic surgery of the external genitalia to correct urinary misdirection was successfully performed 3 months after laparoscopic castration. Standing flank laparoscopic examination was excellent for identification and surgical removal of internal genitalia. Standing flank laparoscopy should be considered for inspection and removal of internal genitalia in intersex horses.

Denys-Drash syndrome, characterized by nephrosis, dysgenetic gonads and a predisposition to Wilms tumor, is due to germline mutations in the WT1 gene. We report the pathologic findings on monozygotic twins, both of whom presented with male pseudohermaphroditism, nephrotic syndrome, and progressed to renal failure and death within the first month of life. Sequence analysis of WT1 demonstrated a G-to-A substitution in exon 8 of the gene (c.1097G > A), resulting in an arginine-to-histidine (R366H) substitution in the second zinc finger domain. To the best of our knowledge, this is only the second set of monozygotic twins with Denys-Drash syndrome reported to date.

Rationale Persistent Mullerian 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 Mullerian duct should be needed. A long-term postoperative follow-up is necessary for assessment of malignant transformation and infertility.

Persistent mullerian duct syndrome (PMDS) is a rare form of male pseudohermaphroditism caused by defects in synthesis or actions of mullerian inhibiting factor characterised by persistence of mullerian duct structures in a normal karyotype male. Transverse testicular ectopia (TTE) is a rare disease in which both testes are located in the same inguinal canal. We report a case of PMDS with TTE in a 1-year-old child who presented with non-palpable testis on right side with hernia on left side. Left herniotomy with bilateral trans-septal orchidopexy was done in this patient.

The diagnosis of Frasier syndrome is based on the association of male pseudohermaphroditism (as a result of gonadal dysgenesis), with steroid-resistant nephrotic syndrome due to focal and segmental glomerular sclerosis (FSGS), which progresses to end-stage renal failure (ESRF) during adolescence or adulthood. Frasier syndrome results from mutations in the Wilms' tumour suppressor gene WT1, which is responsible for alterations in male genital development and podocyte dysfunction. We describe the case of a 7-year-old girl who was referred to the paediatric emergency department with ESRF. Haemodialysis was started immediately because of severe hypertension and hyperkalaemia. In view of the fact that our patient had a past medical history of pseudohermaphroditism, we suspected that the acute presentation in ESRF may be related to a new diagnosis of Frasier syndrome. Our hypothesis was confirmed on examination of the medical records. There had been no medical follow-up for several years and, in particular, no renal imaging or functional assessment had ever been performed. This lack of surveillance explains why our patient presented with ESRF much earlier in this disease than expected and subsequently had to undergo kidney transplantation at a very young age.

Summary A pseudohermaphrodite possesses gonads of one sex, but with external genitalia of the opposite sex. Although cases of male pseudohermaphroditism have been published, there is no report of a monorchid male pseudohermaphrodite. This Case Report documents a 12-year-old monorchid male pseudohermaphrodite displaying stallion-like behaviour, with an elevated serum oestrone sulphate concentration confirming the presence of functional testicular tissue. A complete resolution of all behavioural signs occurred after laparoscopic-assisted castration under general anaesthesia, along with a drop in serum oestrone sulphate concentrations to

Male pseudohermaphroditism and androgen insensitivity syndrome cases have an increased risk of developing testicular cancer due to many factors such as mutations, hormonal disturbances involving gonadotropins and cryptorchidism. We describe the clinical features, diagnosis and treatment of two cases with partial androgen insensitivity syndrome and testicular cancer development, which were handled at the National Cancer Institute of Mexico.

Aim: To identify the genotype of two Indians with male pseudohermaphroditism. Methods: Standard radioimmunoassay procedure was used for estimating hormonal levels. Conventional cytogenetic analysis was carried out for diagnosing the genetic sex in these subjects with genital ambiguity. Molecular analysis was carried out by standard polymerase chain reaction procedure using different sets of primers and reaction conditions specific for the 5αreductase type 2 gene (SRD5A2) gene. Direct sequencing was carried out using the ABI Prism dye terminator sequencing kit and the ABI 310 sequencing apparatus. Results: We found an SRD5A2 gene mutation in exon 5, where arginine is substituted with glutamine (R246Q), in two males with pseudohermaphroditism and ambiguous genitalia from unrelated families. This is the first time this mutation has been reported in individuals from India. Conclusion: Identification of the R246Q mutation of the SRD5A2 gene from two unrelated Indian families possibly extends the founder gene effect. (Asian J Androl 2008 Sep; 10: 815–818)

Resume Introduction Le syndrome d’insensibilite complete aux androgenes est une entite rare. Il est du a une mutation au niveau du recepteur peripherique des androgenes. Nous decrivons une nouvelle mutation au niveau de l’exon 1. Materiels et methodes Nous rapportons l’observation d’une jeune fille de 29 ans ayant un syndrome d’insensibilite aux androgenes decouvert a l’occasion de l’exploration d’une amenorrhee primaire. L’enquete familiale a revele l’atteinte de deux autres cas. Resultats Le diagnostic etait oriente par la clinique et la biologie, et confirme par la biologie moleculaire qui a mis en evidence une nouvelle mutation du gene du recepteur aux androgenes, a type de deletion au niveau de l’exon 1, non decrite auparavant. Conclusion La description d’une nouvelle mutation au niveau du recepteur aux androgenes, permet de mieux comprendre la complexite de cette pathologie. A travers ces observations, des particularites cliniques, biologiques et anatomopathologiques sont decrites.