Disorders Of Sex Development Patients Research Articles

Tumors of bilateral streak gonads in patients with disorders of sex development containing y chromosome material.

The presence of Y chromosome material in patients with disorders of sex development (DSD) has been associated with a high risk of gonadoblastoma. Therefore, gonadectomy is recommended in females with bilateral streak gonads and Y chromosome material. The aim of this study was to present our experience with prophylactic gonadectomy in those patients and evaluate their risk of gonadal tumors. We reviewed the charts of 11 female patients who had bilateral gonadectomy (by laparoscopically in 9 patients, by laparotomy in 2 patients) between 1991 and 2012 at our hospital. Seven patients with Turner syndrome (TS) who carry a Y mosaic karyotype in peripheral blood, 3 patients with Swyer syndrome and one patient with Frasier syndrome were included. All patients had an unambiguous female phenotype. Age at surgery and follow-up ranged from 2 to 23 (mean 11) and 0.5 to 20 (mean 8) yr, respectively. Pathologic examination revealed gonadal tumors in 6 of 11 patients (56%), including 4 with TS, the youngest of which was 2 yr old, one with Swyer syndrome and one with Frasier syndrome. A gonadoblastoma was detected in 8 gonads, and an association of dysgerminoma with gonadoblastoma was detected in 2 gonads. Imaging studies showed no metastasis, and the postoperative course was uneventful in all patients. In our series of DSD patients with bilateral streak gonads and Y chromosome material, the risk of gonadal tumor was high. Considering the early occurrence of gonadoblastoma and its high potential for malignant transformation, early prophylactic gonadectomy is strongly recommended.

A Korean boy with 46,XX testicular disorder of sex development caused by SOX9 duplication.

The 46,XX testicular disorder of sex development (DSD), also known as 46,XX male syndrome, is a rare form of DSD and clinical phenotype shows complete sex reversal from female to male. The sex-determining region Y (SRY) gene can be identified in most 46,XX testicular DSD patients; however, approximately 20% of patients with 46,XX testicular DSD are SRY-negative. The SRY-box 9 (SOX9) gene has several important functions during testis development and differentiation in males, and overexpression of SOX9 leads to the male development of 46,XX gonads in the absence of SRY. In addition, SOX9 duplication has been found to be a rare cause of 46,XX testicular DSD in humans. Here, we report a 4.2-year-old SRY-negative 46,XX boy with complete sex reversal caused by SOX9 duplication for the first time in Korea. He showed normal external and internal male genitalia except for small testes. Fluorescence in situ hybridization and polymerase chain reaction (PCR) analyses failed to detect the presence of SRY, and SOX9 intragenic mutation was not identified by direct sequencing analysis. Therefore, we performed real-time PCR analyses with specific primer pairs, and duplication of the SOX9 gene was revealed. Although SRY-negative 46,XX testicular DSD is a rare condition, an effort to make an accurate diagnosis is important for the provision of proper genetic counseling and for guiding patients in their long-term management.

New insights into disorders of gonad development using whole genome analysis

One of the most fundamental influences on our lives is our sex. Whether we are born as male or female has an enormous impact on our behaviour, reproductive options and disease susceptibility. Consequently, if the sex of a baby is not clear it can create many intractable issues, particularly in terms of medical management. Disorders of Sex Development (DSDs) are congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. The cause of these problems is most often a breakdown of the complex network of gene regulation responsible for proper development of testes or ovaries in the embryo. In the majority of DSD patients the etiology is unknown and they cannot be given an accurate diagnosis. We aim to identify the underlying changes in gonad genes of these DSD patients, provide a diagnosis and gain insights into gonad development. We used microarrays to detect changes in copy number in DSD patients. This approach identified potential novel testis specific regulatory regions in SOX9, a known testis gene. We also showed that deletions and duplications affecting the regulatory sequences of SOX3 can cause it to be ectopically expressed in the developing gonad, allowing it to drive testis development in the absence of SRY in patients with 46,XX testicular DSD. In addition, we have identified mutations in the novel gene, MAP3K1 in patients with 46,XY DSD; implicating a new signal transduction pathway in testis development. We’ve used Massively Parallel Sequencing (MPS) in three different ways. Firstly, we developed a rapid targeted MPS approach allowing in depth analysis of up to 200 gonad genes per DSD patient. Secondly, we used whole exome capture and MPS on several DSD families, trios and single cases. Finally, we employed whole genome MPS on trios with DSD. This work demonstrates the tremendous power of whole genome approaches, especially when combing MPS data with linkage analysis of a large family. Whole genome analysis provides a rapid approach to identification of the disease-causing mutations and molecular diagnosis in patients with DSD as well as providing insights into gonad development and sex differentiation.

Characteristic of patients with disorders of sex development (DSD) in Cipto Mangunkusumo Hospital, Jakarta

Disorder of Sex Development (DSD) is a congenital condition in which development of chromosomal, gonadal or anatomical sex is atypical. They are complex condition related to social stigma, cultural and beliefs in Indonesian population. In Indonesia, there is only a few study regarding characteristic of DSD patients. The aims of our study was to evaluate the characteristic of patients with DSD in Cipto Mangunkusumo Hospital, Jakarta, Indonesia. We retrospectively reviewed the medical records of patients followed up over the period from 2010 to 2012 in Endocrinology Pediatric Clinic, Cipto Mangunkusumo Hospital, Jakarta, Indonesia. We found 74 patients with DSD. In this paper we excluded 29 patients confirmed as Congenital Adrenal Hyperplasia and 3 patients with Turner syndrome. Of 42 patients, 23 (54.8%) patients had 46,XY DSD; 11 (26.2%) patients had sex chromosome DSD; 3 (7.1%) patients had 46,XY DSD, and 5 patients have not done chromosomal analysis. The age when first diagnosed was ranging from newborn to 14 years old. Most cases referred by pediatrician (33.3%) and urologist (23.8%) with frequent complaint were ambiguous genitalia (52.4%) and severe hypospadia (14.3%). The most frequent of phenotype was hypospadia (66.7%). Twenty five (59.5%) of patients have been raised as boy prior to diagnosis. Twelve patients were raised as girls have 46, XY karyotype and 2 patients raised as boys have 46, XX karyotype. Definite diagnosis of 23 patients with 46, XY DSD was found only in 4 (17.4%) patients. The problem regarding lack of definitife diagnosis was related with the high cost of laboratory examination and socioeconomic problem in Indonesia. Our study suggest that the most common cause of DSD in our clinic was 46, XY DSD. Karyotype and clinical phenotype may help in establishing the diagnosis.

Translational Genetics for Diagnosis of Human Disorders of Sex Development

Disorders of sex development (DSDs) are congenital conditions with discrepancies between the chromosomal, gonadal, and phenotypic sex of the individual. Such disorders have historically been difficult to diagnose and cause great stress to patients and their families. Genetic analysis of human samples has been instrumental in elucidating the molecules and pathways involved in the development of the bipotential gonad into a functioning testis or ovary. However, many DSD patients still do not receive a genetic diagnosis. New genetic and genomic technologies are expanding our knowledge of the underlying mechanism of DSDs and opening new avenues for clinical diagnosis. We review the genetic technologies that have elucidated the genes that are well established in sex determination in humans, discuss findings from more recent genomic technologies, and propose a new paradigm for clinical diagnosis of DSDs.

Diagnosis of 5α-Reductase 2 Deficiency: Is Measurement of Dihydrotestosterone Essential?

5α-Reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development (DSD). Traditionally, the diagnosis relies on dihydrotestosterone (DHT) measurement, but the results are often equivocal, potentially leading to misdiagnosis. We reviewed alternative approaches for diagnosis of 5ARD. We conducted a retrospective review of the results of urinary steroid profiling (USP) by GC-MS and mutational analysis of SRD5A2 [steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)] by PCR and direct DNA sequencing of all 46,XY DSD patients referred to our laboratory with biochemical and/or genetic findings compatible with 5ARD. We also performed a literature review on the laboratory findings of all 5ARD cases reported in the past 10 years. Of 16 patients diagnosed with 5ARD between January 2003 and July 2012, 15 underwent USP, and all showed characteristically low 5α- to 5β-reduced steroid metabolite ratios. Four patients had DHT measured, but 2 did not reach the diagnostic cutoff. In all 12 patients who underwent genetic analysis, 2 mutations of the SRD5A2 gene were detected to confirm the diagnosis. Twenty-four publications involving 149 patients with 5ARD were published in the review period. Fewer than half of these patients had DHT tested. Nearly 95% of them had the diagnosis confirmed genetically. 5ARD can be confidently diagnosed by USP at 3 months postnatally and confirmed by mutational analysis of SRD5A2. Interpretation of DHT results may be problematic and is not essential in the diagnosis of 5ARD. We propose new diagnostic algorithms for 46,XY DSD.

Gonadal malignancy in 13 consecutive collected patients with disorders of sex development (DSD) from Semarang (Indonesia)

AimsCaucasian patients with disorders of sex development (DSD) are at a high risk of developing germ cell cancer (GCC). GCC is prominent in young adults in Western countries, while the...

SRY mutation analysis by next generation (deep) sequencing in a cohort of chromosomal Disorders of Sex Development (DSD) patients with a mosaic karyotype

BackgroundThe presence of the Y-chromosome or Y chromosome-derived material is seen in 4-60% of Turner syndrome patients (Chromosomal Disorders of Sex Development (DSD)). DSD patients with specific Y-chromosomal material in their karyotype, the GonadoBlastoma on the Y-chromosome (GBY) region, have an increased risk of developing type II germ cell tumors/cancer (GCC), most likely related to TSPY. The Sex determining Region on the Y gene (SRY) is located on the short arm of the Y-chromosome and is the crucial switch that initiates testis determination and subsequent male development. Mutations in this gene are responsible for sex reversal in approximately 10-15% of 46,XY pure gonadal dysgenesis (46,XY DSD) cases. The majority of the mutations described are located in the central HMG domain, which is involved in the binding and bending of the DNA and harbors two nuclear localization signals. SRY mutations have also been found in a small number of patients with a 45,X/46,XY karyotype and might play a role in the maldevelopment of the gonads.MethodsTo thoroughly investigate the presence of possible SRY gene mutations in mosaic DSD patients, we performed next generation (deep) sequencing on the genomic DNA of fourteen independent patients (twelve 45,X/46,XY, one 45,X/46,XX/46,XY, and one 46,XX/46,XY).Results and conclusionsThe results demonstrate that aberrations in SRY are rare in mosaic DSD patients and therefore do not play a significant role in the etiology of the disease.

Prevalence of c-KIT Mutations in Gonadoblastoma and Dysgerminomas of Patients with Disorders of Sex Development (DSD) and Ovarian Dysgerminomas

Activating c-KIT mutations (exons 11 and 17) are found in 10–40% of testicular seminomas, the majority being missense point mutations (codon 816). Malignant ovarian dysgerminomas represent ∼3% of all ovarian cancers in Western countries, resembling testicular seminomas, regarding chromosomal aberrations and c-KIT mutations. DSD patients with specific Y-sequences have an increased risk for Type II Germ Cell Tumor/Cancer, with gonadoblastoma as precursor progressing to dysgerminoma. Here we present analysis of c-KIT exon 8, 9, 11, 13 and 17, and PDGFRA exon 12, 14 and 18 by conventional sequencing together with mutational analysis of c-KIT codon 816 by a sensitive and specific LightCycler melting curve analysis, confirmed by sequencing. The results are combined with data on TSPY and OCT3/4 expression in a series of 16 DSD patients presenting with gonadoblastoma and dysgerminoma and 15 patients presenting pure ovarian dysgerminomas without DSD. c-KIT codon 816 mutations were detected in five out of the total of 31 cases (all found in pure ovarian dysgerminomas). A synonymous SNP (rs 5578615) was detected in two patients, one DSD patient (with bilateral disease) and one patient with dysgerminoma. Next to these, three codon N822K mutations were detected in the group of 15 pure ovarian dysgerminomas. In total activating c-KIT mutations were found in 53% of ovarian dysgerminomas without DSD. In the group of 16 DSD cases a N505I and D820E mutation was found in a single tumor of a patient with gonadoblastoma and dysgerminoma. No PDGFRA mutations were found. Positive OCT3/4 staining was present in all gonadoblastomas and dysgerminomas investigated, TSPY expression was only seen in the gonadoblastoma/dysgerminoma lesions of the 16 DSD patients. This data supports the existence of two distinct but parallel pathways in the development of dysgerminoma, in which mutational status of c-KIT might parallel the presence of TSPY.

Challenges of Disorders of Sex Development: Diverse Perceptions across Stakeholders

Background/Aims: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or anatomic sex development is atypical. Optimal management is patient- and family-centered and delivered by interdisciplinary teams. The present pilot study elicits concerns held by important stakeholders on issues affecting young patients with DSD and their families. Methods: Content from focus groups with expert clinicians (pediatric urologists (n = 7), pediatric endocrinologists (n = 10), mental health professionals (n = 4), DSD patient advocates (n = 4), and interviews with parents of DSD-affected children (newborn to 6 years; n = 11) was coded and content-analyzed to identify health-related quality of life issues. Results: Key stressors varied across stakeholder groups. In general, family-centered issues were noted more than child-centered. In the child-centered domain, providers worried more about physical functioning; family and advocates emphasized gender concerns and body image. In the family-centered domain, parental concerns about medication management outweighed those of providers. Advocates reported more stressors regarding communication/information than other stakeholders. Conclusion: Variability exists across stakeholder groups in the key concerns affecting young children/families with DSD. Interdisciplinary DSD healthcare team development should account for varying perspectives when counseling families and planning treatment.

A 46,XY Female DSD Patient with Bilateral Gonadoblastoma, a Novel SRY Missense Mutation Combined with a WT1 KTS Splice-Site Mutation

Patients with Disorders of Sex Development (DSD), especially those with gonadal dysgenesis and hypovirilization are at risk of developing malignant type II germ cell tumors/cancer (GCC) (seminoma/dysgerminoma and nonseminoma), with either carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesion. In 10–15% of 46,XY gonadal dysgenesis cases (i.e., Swyer syndrome), SRY mutations, residing in the HMG (High Mobility Group) domain, are found to affect nuclear transport or binding to and bending of DNA. Frasier syndrome (FS) is characterized by gonadal dysgenesis with a high risk for development of GB as well as chronic renal failure in early adulthood, and is known to arise from a splice site mutation in intron 9 of the Wilms’ tumor 1 gene (WT1). Mutations in SRY as well as WT1 can lead to diminished expression and function of SRY, resulting in sub-optimal SOX9 expression, Sertoli cell formation and subsequent lack of proper testicular development. Embryonic germ cells residing in this unfavourable micro-environment have an increased risk for malignant transformation. Here a unique case of a phenotypically normal female (age 22 years) is reported, presenting with primary amenorrhoea, later diagnosed as hypergonadotropic hypogonadism on the basis of 46,XY gonadal dygenesis with a novel missense mutation in SRY. Functional in vitro studies showed no convincing protein malfunctioning. Laparoscopic examination revealed streak ovaries and a normal, but small, uterus. Pathological examination demonstrated bilateral GB and dysgerminoma, confirmed by immunohistochemistry. Occurrence of a delayed progressive kidney failure (focal segmental glomerular sclerosis) triggered analysis of WT1, revealing a pathogenic splice–site mutation in intron 9. Analysis of the SRY gene in an additional five FS cases did not reveal any mutations. The case presented shows the importance of multi-gene based diagnosis of DSD patients, allowing early diagnosis and treatment, thus preventing putative development of an invasive cancer.

Disorders of Sex Development: Challenges for the Future

The perpetual challenge in the diagnosis and management of patients with disorders of sex development (DSD), to paraphrase the adage, is that as our circle of knowledge in the genetic mechanisms of DSD expands, so does the circumference of darkness surrounding it. New technologies (comparative genomic hybridization, sequencing by hybridization, and next generation sequencing) are rapidly generating massive amounts of information on the pathogenesis of DSD (1). The caveat is that identifying a pathogenic mutation may not predict the clinical picture because phenotype can be highly variable, even within the same family (2). Oligogenic modulators, developmental switches, epigenetic influences, environmental stimuli, and even imbalanced cis-regulation of mutant vs. wild-type alleles when mutations are present in a heterozygous state may also be contributing factors to the variable expression of phenotype (3). A major step forward in organizing the molecular and clinical information was the recent change in nomenclature and classification of DSD. In 2006, the Pediatric Endocrine Society (formerly known as the Lawson and Wilkins Pediatric Endocrine Society) and the European Society for Pediatric Endocrinology consensus group defined DSD as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical, and broadly classified DSD into three groups based upon cytogenetic, hormonal, gonadal histology, and clinical findings: 46,XY DSD, 46,XX DSD, and sex chromosome DSD (4). The classification reflected the natural history of the diagnostic process in which the sex chromosomes are the usual starting point for investigations of a child with atypical genitalia. As our genetic and endocrine understanding of unclassified or syndromic conditions improves, the DSD classification, which continues to gain wide acceptance across the globe (5), has the flexibility to incorporate them into its current structure. But there is still a long way to go to where the genetic information can be used to predict long-term outcomes to provide personalized care for the DSD patient. In some DSD, clinical diagnosis can be confirmed by hormonal and molecular testing. For example, in complete androgen insensitivity syndrome there is an 80 – 90% chance that a 46,XY infant with normal female genitalia and normal testosterone synthesis will have a mutation in androgen receptor gene (6). Similarly, the majority of 46,XX presenting with virilized genitalia will have congenital adrenal hyperplasia with a mutation in CYP21A2 where genotype-phenotype correlations are excellent (7). In cases of XY DSD with partially virilized genitalia, a molecular diagnosis has been relatively elusive so that diagnosis is guided by a thorough clinical, biochemical, and anatomical evaluation of the affected infant. For instance, only about 20% of these cases associated with normal androgen synthesis will have a mutation in the androgen receptor gene (6). Discordance between molecular changes and functional in vitro transactivation studies complicate even further the efforts for attributing the particular DSD phenotype to the identified gene change. Furthermore, such functional studies continue to remain in the realms of research laboratories, and their large-scale clinical utility remains unclear. The recent identification of mutations associated with DSD in a poorly characterized MAPK sig-

Satisfaction With Genital Surgery and Sexual Life of Adults With XY Disorders of Sex Development

Disorders of sex development (DSD) are rare disorders defined as discrepancy of chromosomal, gonadal, or anatomic sex. Prenatal lack of androgens or partial androgenization results in atypical development of the genitalia in individuals with XY DSD. In the past, most XY DSD individuals with ambiguous genitalia were assigned to the female sex and often underwent early feminizing treatment, including constructive genital surgery to allow heterosexual intercourse, gonadectomy, and hormone therapy. Few outcome studies of the effect of early feminizing genital surgery on sexual satisfaction and performance among adults with XY DSD have been performed. There is increasing evidence, primarily from DSD patients, that questions the benefit of early feminization treatment. The aim of this study was to evaluate satisfaction with reconstructive genital surgery and sexual life among adults with XY DSD. A total of 57 individuals with XY DSD enrolled in the German multicenter clinical evaluation study of DSD were interviewed using a condition-specific questionnaire assessing standardized measures of satisfaction with treatment. The sexual life and sexual problems evaluated included the following: satisfaction with overall sex life, present partnership, previous sexual partners, decreased sexual desire, problems with sexual arousal, and pain during intercourse (dyspareunia). The individuals were divided into 3 subgroups: (1) XY DSD complete females (XY DSD-CF) or individuals with complete androgen insensitivity syndrome, raised as females; (2) XY DSD partially androgenized females (XY DSD-PF), raised as females; and (3) XY DSD partially androgenized males, assigned to the male gender. Some comparisons were done with a control group of normal individuals surveyed about sexual satisfaction. There was substantial dissatisfaction with overall treatment among individuals with XY DSD-PF (43.3%) and XY DSD-CF (56.2%). XY DSD-PF individuals who had feminization surgery expressed high dissatisfaction, with the functional result (47.1%) and clitoral arousal (47.4%) compared with controls. Individuals with XY DSD-PF reported a substantially higher proportion of having female sexual partners (9.1%) or partners of both sexes (18.2%) and dyspareunia (56.5%) compared with female controls. XY DSD-CF individuals had decreased sexual desire (70.6%), arousal (52.9%), and dyspareunia (56.3%) compared with controls. Most individuals with complete androgen insensitivity syndrome reported significant sexual problems compared with controls; there was decreased desire (81.8%), arousal (63.6%), and dyspareunia (70%) (all P < 0.05). These findings indicate that use of early feminizing surgery in XY DSD individuals should be avoided or minimized, and that surgical correction should be performed primarily in puberty or adulthood with the parents and patients consent. The decision of sex of rearing might not have been appropriate in some cases, and the choice of gender of rearing can be postponed in some families. Information about the disorder should be provided to DSD-affected individuals and their families in an age-appropriate and sensible manner. Patients and their families should be followed from childhood to adolescence and adulthood, and should receive multidisciplinary care with psychological support and input from other patients and families with DSD.

1527 GONADAL TUMOR DETECTION AND TREATMENT IN PATIENTS WITH DISORDER OF SEX DEVELOPMENT (DSD) LONG-TERM ONCOLOGICAL OUTCOMES

You have accessJournal of UrologyPediatrics: Congenital Anomalies - Lower Urinary Tract & Genitalia I1 Apr 20121527 GONADAL TUMOR DETECTION AND TREATMENT IN PATIENTS WITH DISORDER OF SEX DEVELOPMENT (DSD) LONG-TERM ONCOLOGICAL OUTCOMES Lorena Oliveira, Marcos Machado, Giovanni Marchini, Alessandro Tavares, Maria Helena Sircili, Sorahia Domenice, Elaine Costa, Francisco Denes, Berenice Mendonça, and Miguel Srougi Lorena OliveiraLorena Oliveira Sao Paulo, Brazil More articles by this author , Marcos MachadoMarcos Machado Sao Paulo, Brazil More articles by this author , Giovanni MarchiniGiovanni Marchini Sao Paulo, Brazil More articles by this author , Alessandro TavaresAlessandro Tavares Sao Paulo, Brazil More articles by this author , Maria Helena SirciliMaria Helena Sircili Sao Paulo, Brazil More articles by this author , Sorahia DomeniceSorahia Domenice Sao Paulo, Brazil More articles by this author , Elaine CostaElaine Costa Sao Paulo, Brazil More articles by this author , Francisco DenesFrancisco Denes Sao Paulo, Brazil More articles by this author , Berenice MendonçaBerenice Mendonça Sao Paulo, Brazil More articles by this author , and Miguel SrougiMiguel Srougi Sao Paulo, Brazil More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1295AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To expose a 18-year experience in the management of DSD patients with gonadal tumors (GT). METHODS From 1993 to 2011, 14 DSD patients were found to have GT. Mean age at diagnosis was 25.4 ± 10.8 (6.8-43.7) years and social sex was female in 9. Clinical diagnosis was Turner's syndrome in 2, gonadal dysgenesis in 7 and Frasier syndrome, complete and partial androgen insensivity syndrome, 17-beta-hydroxysteroid dehydrogenase deficiency and Mullerian inhibiting factor deficiency in 1 each. Karyotype was 46XY in 11, 45X/46XY in 2 and 46XY/47XYY in 1. Mean follow-up time was 96.2 ± 56.7 (21.1–186.9) months. RESULTS Diagnosis was made by preoperative evaluation or as surgical finding. Laparoscopic gonadectomy was performed in 8 patients. Open gonadal/ductal structures resection was performed by inguinotomy in 2 and through an abdominal incision in 4 patients. Of these 6 patients, 2 underwent laparoscopic excision of remanescent intra-abdominal structures. Pathologic examination revealed gonadoblastoma associated with intratubular neoplasia in 6 patients (3 bilateral), 2 dysgerminomas, 2 seminomas, 2 non-seminomas, 1 Leydig and 1 Sertoli cel tumor. One patient with dysgerminoma and one with non-seminoma underwent adjuvant chemotherapy. No patient had disease recurrence and overall survival was 100%. CONCLUSIONS GT in patients with DSD are clinically unapparent and demand accurate investigation and precise diagnosis. Laparoscopic evaluation of intra-abdominal structures allows therapeutic or prophylactic resection whenever advised. Gonadectomy offers exceptional oncological outcomes in this population. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e618 Peer Review Report Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lorena Oliveira Sao Paulo, Brazil More articles by this author Marcos Machado Sao Paulo, Brazil More articles by this author Giovanni Marchini Sao Paulo, Brazil More articles by this author Alessandro Tavares Sao Paulo, Brazil More articles by this author Maria Helena Sircili Sao Paulo, Brazil More articles by this author Sorahia Domenice Sao Paulo, Brazil More articles by this author Elaine Costa Sao Paulo, Brazil More articles by this author Francisco Denes Sao Paulo, Brazil More articles by this author Berenice Mendonça Sao Paulo, Brazil More articles by this author Miguel Srougi Sao Paulo, Brazil More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Screening of MAMLD1 Mutations in 70 Children with 46,XY DSD: Identification and Functional Analysis of Two New Mutations

More than 50% of children with severe 46,XY disorders of sex development (DSD) do not have a definitive etiological diagnosis. Besides gonadal dysgenesis, defects in androgen biosynthesis, and abnormalities in androgen sensitivity, the Mastermind-like domain containing 1 (MAMLD1) gene, which was identified as critical for the development of male genitalia, may be implicated. The present study investigated whether MAMLD1 is implicated in cases of severe 46,XY DSD and whether routine sequencing of MAMLD1 should be performed in these patients.Seventy children with severe non-syndromic 46,XY DSD of unknown etiology were studied. One hundred and fifty healthy individuals were included as controls. Direct sequencing of the MAMLD1, AR, SRD5A2 and NR5A1 genes was performed. The transactivation function of the variant MAMLD1 proteins was quantified by the luciferase method.Two new mutations were identified: p.S143X (c.428C>A) in a patient with scrotal hypospadias with microphallus and p.P384L (c.1151C>T) in a patient with penile hypospadias with microphallus. The in vitro functional study confirmed no residual transactivating function of the p.S143X mutant and a significantly reduced transactivation function of the p.P384L protein (p = 0.0032). The p.P359S, p.N662S and p.H347Q variants are also reported with particularly high frequency of the p.359T- p.662G haplotype in the DSD patients.Severe undervirilization in XY newborns can reveal mutations of MAMLD1. MAMLD1 should be routinely sequenced in these patients with otherwise normal AR, SRD5A2 and NR5A1genes.

Update on disorders of sex development

To review the recent information regarding disorders of sex development (DSD) which contribute to, as well as highlight, the need for greater understanding of genetic mutations and the dire need for specific outcome information. New information is primarily related to the identification of genetic mutations and other gene variations that impact reproductive system development. These new data add to the increasingly complex list of genes and the multigenetic effects involved in DSD. Several reviews outline the approach to diagnosis and management of the patient with DSD and the importance of a multidisciplinary team. These reviews continue to demonstrate the lack of specific guidelines for complex DSD patients for whom sex assignment is problematic. Although genetic research continues to define new and multigenetic factors involved in the development of DSD, this review of the medical literature also underscores the fact that scientific understanding remains inadequate in many areas of DSD to provide solid guidelines for approaching the more controversial questions in the DSD patient. Accordingly, the need for larger, outcome studies using subjects with verified diagnoses are needed. Optimally, these studies would account for potentially confounding differences in genetic, social, and psychological factors to help answer the pressing question facing every clinician dealing with DSD patients - what is the relationship between medical decision-making (such as sex assignment and genital surgery) and future quality of life and adaptation.

Delayed Recognition of Disorders of Sex Development (DSD): A Missed Opportunity for Early Diagnosis of Malignant Germ Cell Tumors

Disorders of sex development (DSD) are defined as a congenital condition in which development of chromosomal, gonadal or anatomical sex is atypical. DSD patients with gonadal dysgenesis or hypovirilization, containing part of the Y chromosome (GBY), have an increased risk for malignant type II germ cell tumors (GCTs: seminomas and nonseminomas). DSD may be diagnosed in newborns (e.g., ambiguous genitalia), or later in life, even at or after puberty. Here we describe three independent male patients with a GCT; two were retrospectively recognized as DSD, based on the histological identification of both carcinoma in situ and gonadoblastoma in a single gonad as the cancer precursor. Hypospadias and cryptorchidism in their history are consistent with this conclusion. The power of recognition of these parameters is demonstrated by the third patient, in which the precursor lesion was diagnosed before progression to invasiveness. Early recognition based on these clinical parameters could have prevented development of (metastatic) cancer, to be treated by systemic therapy. All three patients showed a normal male 46,XY karyotype, without obvious genetic rearrangements by high-resolution whole-genome copy number analysis. These cases demonstrate overlap between DSD and the so-called testicular dysgenesis syndrome (TDS), of significant relevance for identification of individuals at increased risk for development of a malignant GCT.

Mammalian sex determination—insights from humans and mice

Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Many of the genes required for gonad development have been identified by analysis of DSD patients. However, the use of knockout and transgenic mouse strains have contributed enormously to the study of gonad gene function and interactions within the development network. Although the genetic basis of mammalian sex determination and differentiation has advanced considerably in recent years, a majority of 46,XY gonadal dysgenesis patients still cannot be provided with an accurate diagnosis. Some of these unexplained DSD cases may be due to mutations in novel DSD genes or genomic rearrangements affecting regulatory regions that lead to atypical gene expression. Here, we review our current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models.

Application of the New Classification on Patients with a Disorder of Sex Development in Indonesia

Disorder of sex development (DSD) patients in Indonesia most often do not receive a proper diagnostic evaluation and treatment. This study intended to categorize 88 Indonesian patients in accordance with the new consensus DSD algorithm. Diagnostic evaluation including clinical, hormonal, genetic, imaging, surgical, and histological parameters was performed. Fifty-three patients were raised as males, and 34 as females. Of 22 patients with 46, XX DSD, 15 had congenital adrenal hyperplasia, while in one patient, an ovarian Leydig cell tumor was found. In all 58 46, XY DSD patients, 29 were suspected of a disorder of androgen action (12 with an androgen receptor mutation), and in 9, gonadal dysgenesis was found and, in 20, severe hypospadias e.c.i. Implementation of the current consensus statement in a resource-poor environment is very difficult. The aim of the diagnostic workup in developing countries should be to end up with an evidence-based diagnosis. This is essential to improve treatment and thereby to improve the patients' quality of life.

A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development

Disorders of sex development (DSD) are congenital conditions where chromosomal, gonad or genital development is atypical. In a significant proportion of 46,XY DSD cases it is not possible to identify a causative mutation, making genetic counseling difficult and potentially hindering optimal treatment. Here, we describe the analysis of a 46,XY DSD patient that presented at birth with ambiguous genitalia. Histological analysis of the surgically removed gonads showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. We screened genomic DNA from this patient for deletions and duplications using an Illumina whole-genome SNP microarray. This analysis revealed a heterozygous deletion within the WWOX gene on chromosome 16, removing exons 6-8. Analysis of parental DNA showed that the deletion was inherited from the mother. cDNA analysis confirmed that the deletion maintained the reading frame, with exon 5 being spliced directly onto exon 9. This deletion is the first description of a germline rearrangement affecting the coding sequence of WWOX in humans. Previously described Wwox knockout mouse models showed gonadal abnormalities, supporting a role for WWOX in human gonad development.