Dysgenetic Testes Research Articles

Mixed Gonadal Dysgenesis: A Narrative Literature Review and Clinical Primer for the Urologist.

Mixed gonadal dysgenesis is a difference of sex development that is often confused with other conditions. Individuals have a 45,X/46,XY karyotype. Gonads are characterized by a streak gonad and a dysgenetic testis at varying levels of descent. Persistent Müllerian structures are typical (eg, hemi-uterus). There is significant phenotypic heterogeneity of the internal and external genitalia that, together with different interpretations of the definition, have contributed to a poor understanding of the condition among pediatric urologists. Mixed gonadal dysgenesis is one manifestation of the 45,X/46,XY karyotype. 45,X/46,XY mosaicism can also be associated with typical female or male external genitalia. This review aims to clarify the mixed gonadal dysgenesis definition and to provide urologists with diagnostic and management considerations for affected individuals. We searched 3 medical databases for articles related to mixed gonadal dysgenesis. Two hundred eighty-seven full-text abstracts and manuscripts were reviewed for content pertinent to: (1) clarifying the definition of mixed gonadal dysgenesis, and (2) describing the following related to the care of affected individuals: prenatal and neonatal evaluation and management, genital surgery, gonadal malignancy risk and management, fertility, gender dysphoria/incongruence, puberty and long-term outcomes, systemic comorbidities, and transitional care. Fifty articles were included. Key points and implications for each of the above topics were summarized. Mixed gonadal dysgenesis exists on a wide phenotypic spectrum and management considerations reflect this heterogeneity. Care for individuals with mixed gonadal dysgenesis is complex, and decisions should be made in a multidisciplinary setting with psychological support.

PMON311 45,X/46,XY mixed gonadal dysgenesis: a case report from Saudi Arabia

Abstract Introduction Mixed gonadal dysgenesis is a sex developmental disorder where the gonads are abnormal from there being some cells with XY chromosomes and some with just asingle X, known as chromosome Y mosaicism. This results in a wide range of male/female genitalia that are not typically, or clearly, male or female The case: 3 years old Saudi boy was born term to 35 year old G5P5 Normal anti natal and history of consanguinity. Birth weight 2 kilogram and found to have genital ambiguity in the form of short phallus structure and hypospiadius testis were felt at the right inguinal canal. his investigation showed abnormal chromosomes 45×46XY musiac . Mother chromosomes were 46XX normal female karyotype. normal siblings and Wes WES: CNV DESCRIPTION*: seq[GRCh37] Yp11.31q11.23 (mosaic∼50% of the cells) SIZE (KB): ∼26Mb, GENE COUNT**: 116, INTERPRETATION***: Pathogenic. RELATED DISORDER: 45,X/46,XY mixed gonadal dysgenesis The radiological investigations showed small oval shaped mass over the right inguinal canal 0.8/0.6/0.8 cm in size .the left testis couldn't be seen . And Genetogram showed presence of vagina and small uterus. his laboratory investigations showed at age of 2.5 years LH: less than o.3 and his Testosterone basal was less than 0.09 and Testosterone post HCG 8.29 which should excellent response to HCG.. the case was discussed with the paediatric urologist and the decision was as per the anatomical finding and results of the stimulated Testosterone to give Testosterone injections and asses the response. The child respond very well to the testosterone treatment which leads to improvement in the size and length of the phallus. Discussion mixed gonadal dysgenesis is one of the causes of DSD .45, X/ 46, XY mosaic: At birth around 90 per cent of babies with 45,X/46,XY have normal-appearing external male genitals, five per cent have normal-appearing female genitals and in five percent the external reproductive organs are neither fully male nor fully female. They may find one or two gonads that are very inadequate testes, possibly with some ovary-like tubules present. They may find one streak gonad and one immature, dysgenetic or normal testis. They may find an internal vagina, cervix and uterus, although these are usually quite small compared to a normal female. Some people with a 45,X/46,XY karyotype have reduced fertility and some are infertile. No judgment can be made about fertility until well after puberty in the apparently normal males. Children with a 45,X/46,XY karyotype can have any of the medical conditions that are more common among girls with Turner syndrome (who have a 45,X karyotype), which includes heart and disorders, autoimmune disorders and short stature. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Variation of Gonadal Dysgenesis and Tumor Risk in Patients With 45,X/46,XY Mosaicism

To describe the gonadal features of patients with 45,X/46,XY mosaicism, and to evaluate the prevalence of gonadal tumor in different phenotypes. The medical records of consecutive patients with 45,X/46,XY karyotype or its variants who had undergone gonadal biopsy or gonadectomy at a single institute between 1996 and 2017 were retrospectively reviewed. Of 34 patients with 45,X/46,XY mosaicism, a unilateral dysgenetic testis and a contralateral streak gonad was detected in 20 patients (59%), bilateral streak gonads in 9 (26%), and bilateral dysgenetic testes in 5 (15%). A gonad composed of both streak and dysgenetic testicular portions was observed in 7 gonads of 6 patients. All streak gonads were removed, and bilateral gonadectomy was performed in 15 patients raised as girls. Pathologic examination revealed gonadal tumors in 6 of the 34 (18%) patients, including a gonadoblastoma in 7 gonads among 5 patients and an association of dysgerminoma with gonadoblastoma in 1 gonad. All 6 patients who developed gonadal tumor had female genitalia. Postoperative course was uneventful except 1 boy. A seminoma was developed in his soritaly scrotal testis at the age of 16 years. The prevalence of gonadal tumor in patients with 45,X/46,XY mosaicism may vary according to the phenotype, and high in patients with female phenotype. Considering the increased risk of gonadal tumors in such patients, early investigation and individual management, including prophylactic gonadectomy, are recommended. In male patients, a close follow-up of the preserved testes is mandatory until adulthood.

The spectrum of 45,X/46,XY mosaicism in Taiwanese children: The experience of a single center.

45,X/46,XY mosaicism is a rare sex chromosome abnormality. Here, we present our experience in the management of 45,X/46,XY Taiwanese children. We enrolled 19 patients from January 1981 to September 2016. The diagnosis of 45,X/46,XY mosaicism was made by karyotyping peripheral blood lymphocytes. All medical records were thoroughly reviewed. Of the 19 patients, 16 were reared as females and 3 as males. The age at diagnosis ranged from 1 month to 15 years and 9 months. Atypical genitalia, short stature, and Turner stigmata were common manifestations. No patient exhibited a cardiac malformation but 29% had renal malformations and 12.5% had autoimmune thyroid disease who developed thyroid dysfunction later. Nine girls with short stature received growth hormone therapy and their height standard deviation score rose from -3.4±1.1 to -1.4±0.9 in adulthood (P<0.01). The gonadal phenotypes included bilateral streak gonads in nine patients, a streak gonad with contralateral gonadal agenesis in one, mixed gonadal dysgenesis in five, bilateral dysgenetic testes in two, and bilateral gonadoblastomas in one. The 45,X/46,XY phenotype varies widely and a high index of suspicion is important to ensure early diagnosis. Cardiac and renal malformations should be screened ultrasonically at diagnosis and thyroid status should be monitored annually. Growth hormone effectively improves adult height in short girls. Prophylactic gonadectomy is indicated for those with intra-abdominal streaks or dysgenetic gonads to prevent the development of a malignancy.

Management of pediatric patients with DSD and ambiguous genitalia: Balancing the child's moral claims to self-determination with parental values and preferences

A central ethical dilemma in management of the patient with a disorder of sex development (DSD) is the potential conflict between respect for the fundamental right of the child for physical and emotional integrity and self-determination, and the right of parents to serve as surrogate decision-makers and act in their child's best interest. Over the past 2 years we have encountered three complex DSD cases on the spectrum of mixed gonadal dysgenesis to ovotesticular DSD in which gender assignment and therefore optimal surgical management was uncertain. All patients had mosaic karyotypes with Y chromosome, dysgenetic ovary and dysgenetic testis, a urogenital sinus, and prominent phallus. In all three cases a team approach was taken to assess functional potential and risks along either gender pathway and to develop a spectrum of treatment options for parental consideration, including: 1. masculinization with removal of dysgenetic ovary; 2. initial vaginoplasty but with retention of the phallus (±bilateral gonadectomy); 3. initial vaginoplasty with "burial" of corporal bodies (Pippi Salle procedure) (±bilateral gonadectomy); 4. full feminization: vaginoplasty and clitoroplasty (with bilateral gonadectomy); 5. no surgical intervention. In all three cases, after consideration of risks and benefits of all options, parents selected option 2: gonadectomy to eliminate tumor risk and vaginoplasty, taking advantage of the child's young age to exteriorize urinary and reproductive tracts to avoid incontinence and infection and supporting parental bias toward female gender, but preservation of phallic structures to ensure a male option should the patient later declare a male gender identity. Parents of the three patients were contacted post-operatively (at 7, 17, and 22 months) for follow-up. All (3/3) regarded their child's development and wellbeing positively, and their own decisions regarding gender assignment and surgical plan favorably. All (3/3) regarded the team advisory process as balanced and supportive. In the setting of exposure of the neonatal brain to testosterone, vaginoplasty and phallic preservation afforded a balance between parental preferences and preservation of anatomic options, allowing potential reconstruction of male or female phenotype as gender identity is ascertained thereby respecting both parent and patient rights. Parents valued a spectrum of options, transparency, and the team decision-making process.

A novel, homozygous mutation in desert hedgehog (DHH) in a 46, XY patient with dysgenetic testes presenting with primary amenorrhoea: a case report

BackgroundDesert hedgehog (DHH) mutations have been described in only a limited number of individuals with 46, XY disorders of sex development (DSD) presenting as either partial or complete gonadal dysgenesis. Gonadal tumours and peripheral neuropathy have been associated with DHH mutations. Herein we report a novel, homozygous mutation of DHH identified through a targeted, massively parallel sequencing (MPS) DSD panel, in a patient presenting with partial gonadal dysgenesis. This novel mutation is two amino acids away from a previously described mutation in a patient who presented with complete gonadal dysgenesis. Adding to the complexity of work-up, our patient also expressed gender identity concern.Case presentationA 14-year-old, phenotypic female presented with primary amenorrhoea and absent secondary sex characteristics. Investigations revealed elevated gonadotrophins with low oestradiol, testosterone of 0.6 nmol/L and a 46, XY karyotype. Müllerian structures were not seen on pelvic ultrasound or laparoscopically and gonadal biopsies demonstrated dysgenetic testes without neoplasia (partial gonadal dysgenesis). The patient expressed gender identity confusion upon initial notification of investigation findings. Formal psychiatric evaluation excluded gender dysphoria. Genetic analysis was performed using a targeted, MPS DSD panel of 64 diagnostic and 927 research candidate genes. This identified a novel, homozygous mutation in exon 2 of DHH (DHH:NM_021044:exon2:c.G491C:p.R164P). With this finding our patient was screened for the possibility of peripheral neuropathy which was not evident clinically nor on investigation. She was commenced on oestrogen for pubertal induction.ConclusionThe evaluation of patients with DSD is associated with considerable psychological distress. Targeted MPS enables an affordable and efficient method for diagnosis of 46, XY DSD cases. Identifying a genetic diagnosis may inform clinical management and in this case directed screening for peripheral neuropathy. In addition to the structural location of the mutation other interacting factors may influence phenotypic expression in homozygous DHH mutations.

Male pseudohermaphroditism with 45,X/46,X,idic(Y) karyotype: a case presenting with dysgenetic testis on one side and almost normally sized testis on the other side

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Presence of Germ Cells in Disorders of Sex Development: Implications for Fertility Potential and Preservation

We sought to determine the presence of germ cells in the gonads of patients with disorders of sex development to establish whether preservation of germ cells for future fertility potential is possible. We hypothesized that germ cells are present but vary by age and diagnosis. We reviewed histology from patients with disorders of sex development who underwent gonadectomy/biopsy from 2002 to 2014 at a single institution for pathological classification of the gonad, composition of gonadal stroma and germ cell presence. A total of 44 patients were identified and germ cells were present in 68%. The presence and average number of germ cells per mm2 were analyzed by gonad type and diagnosis. By gonad type all ovotestes, most testes, ovaries and dysgenetic testes, and 15% of streak gonads had germ cells present. By diagnosis germ cells were present in all patients with complete androgen insensitivity syndrome, Denys-Drash syndrome, SRY mutation, mixed gonadal dysgenesis, ovotesticular conditions and StAR (steroid acute regulatory protein) deficiency, in some patients with persistent müllerian duct syndrome, XO/XY Turner syndrome and disorders of sex development not otherwise specified, and in none with complete or partial gonadal dysgenesis. Germ cells were present in the gonads of 88% of patients 0 to 3 years old, 50% of those 4 to 11 years old and 43%of those older than 12 years. Germ cells were present in the majority of our cohort and the presence decreased with age. This novel, fertility driven evaluation of germ cell quantity in a variety of disorders of sex development suggests that fertility potential may be greater than previously thought. Further studies must be done to evaluate a larger population and examine germ cell quality to determine the viability of these germ cells.

A novel morphological approach to gonads in disorders of sex development

AbstractDisorders of sex development are defined as congenital conditions with discordance between the phenotype, the genotype, the karyotype, and the hormonal profile. The disorders of sex development consensus classification established in 2005 are mainly based on chromosomal and biological data. However, histological anomalies are not considered. The aims of this study were to define the specific pathological features of gonads in various groups of disorders of sex development in order to clarify the nosology of histological findings and to evaluate the tumor risk in case of a conservative approach. One hundred and seventy-five samples from 86 patients with disorders of sex development were analyzed following a strict histological reading protocol. The term ‘gonadal dysgenesis' for the histological analysis was found confusing and therefore excluded. The concept of ‘dysplasia' was subsequently introduced in order to describe the architectural disorganization of the gonad (various degrees of irregular seminiferous tubules, thin albuginea, fibrous interstitium). Five histological types were identified: normal gonad, hypoplastic testis, dysplastic testis, streak gonad, and ovotestis. The analysis showed an association between undifferentiated gonadal tissue, a potential precursor of gonadoblastoma, and dysplasia. Dysplasia and undifferentiated gonadal tissue were only encountered in cases of genetic or chromosomal abnormality (‘dysgenesis' groups in the disorders of sex development consensus classification). ‘Dysgenetic testes', related to an embryonic malformation of the gonad, have variable histological presentations, from normal to streak. Conversely, gonads associated with hormonal deficiencies always display a normal architecture. A loss of expression of AMH and α-inhibin was identified in dysplastic areas. Foci of abnormal expression of the CD117 and OCT4 immature germ cells markers in dysplasia and undifferentiated gonadal tissue were associated with an increased risk of neoplasia. This morphological analysis aims at clarifying the histological classification and gives an indication of tumor risk of gonads in disorders of sex development.

NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations

Mutations in the NR5A1 gene, which encodes the steroidogenic factor 1 (SF1), are responsible for different phenotypes of disorders of sex development (DSD), such as bilateral anorchia and hypospadias. Furthermore, they can be associated with primary amenorrhea, premature ovarian failure, male infertility, adrenal tumors, and endometriosis. Direct sequencing of the 7 NR5A1 exons including ∼1,000 bp of the 5′-upstream and 3′-downstream regions and all intron-exon boundaries was performed in patients with DSD. Three different in silico tools were used to assess the consequences of a splice site mutation. As a result, 3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis: p.Lys38* and p.Leu80Trpfs*8 lead to premature translation termination codons within the SF1 DNA-binding domain, and the intronic nucleotide substitution c.1138+1G>T at the intron 6 donor splice site is considered to modify correct splicing. We assume that the anomalous mRNA produced as a result of p.Lys38* and p.Leu80Trpfs*8 will be degraded by nonsense-mediated mRNA decay even before translation, leading to SF1 haploinsufficiency. The c.1138+1G>T mutation is expected to produce a truncated protein. Heterozygous SF1 loss-of-function mutations in these cases resulted in mild DSD manifestations, such as dysgenetic testes, spontaneous puberty, and preserved adrenal function.

Tumor risk of children with 45,X/46,XY gonadal dysgenesis in relation to their clinical presentations: Further insights into the gonadal management

ObjectiveTo investigate the risk of gonadal germ cell neoplasms (GCN) in children with 45,X/46,XY gonadal dysgenesis and its relation to the clinical presentations. MethodsWe conducted a retrospective study reviewing the clinical and gonadal features of all consecutive children with 45,X/46,XY gonadal dysgenesis who received gonadal management in a tertiary center from 1985 to 2015. Study subjects were divided into Group I(significant genitalia anomaly), Group II(female phenotype) and Group III(male phenotype). Results21 children were studied (Group I=8; Group II=11; Group III=2). All 19 children of Group I and II eventually underwent bilateral gonadectomy. One patient of Group III underwent gonadal biopsy which showed increase in fibrous tissue in the testes without any GCN. 3/8(37.5%) and 6/11(54.5%) of patients in Group I and II respectively had either gonadoblastoma (GB) or carcinoma-in-situ (CIS) or both affecting one or both gonads. Among Group I patients, the 4 dysgenetic testes affected by CIS in 3 patients were intraabdominal (n=1), inguinal (n=1) and scrotal (n=2) in positions. Among Group II patients, 6/20 streak gonads had GB and 2/2 dysgenetic testes had GB or CIS. Conclusions45,X/46,XY children with significant genitalia anomaly or female phenotype are both at high risk of gonadal GCN.

The risk of neoplasm associated with dysgenetic testes in prepubertal and pubertal/adult patients.

In patients with Y-chromosome in the karyotype, partial gonadal dysgenesis and disorders of male reproductive sex organs development are usually resected in childhood because of the high risk of germ cell tumours (GCT). In patients with Y-chromosome, complete gonadal dysgenesis and female genitalia gonadectomy is performed markedly later. However, due to the relatively low number of adult patients with preserved dysgenetic gonads, the true risk of neoplasm is unknown. The aim of the study was to evaluate the prevalence of neoplasia in dysgenetic gonads of children and adults with Y-chromosome in a retrospective study. A review of medical documentation of 94 patients with disorders of sex development (DSD), Y-chromosome and gonadal dysgenesis (GD), aged 1.2-32 years (47 prepubertal, 1.2-10 years; 47 pubertal/adult, 13-32 years), was conducted. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were determined. Bilateral gonadectomy was performed in 73.4% of patients, and unilateral gonadectomy with biopsy of the contralateral gonad in 26.4%. All gonadal tissues were subjected to immunohistochemical evaluation with antibodies against PLAP and OCT3/4 (markers of malignant germ cells, but also foetal multipotent germ cells), while gonads of prepubertal patients were examined by c-KIT, as well. Streak gonads were identified on both sides (complete GD) in 30.8%, a streak gonad on one side and an underdeveloped testis on the other (asymmetric GD) in 38.3%, and underdeveloped testicular structure on both sides (partial GD) in 30.8% of cases. Germ cell neoplasia was found in 53.2% of patients (51.1% in children, 55.3% in pubertal/adults). Invasive GCT were identified in 11.7% of cases, of which 90.9% were in pubertal/adult patients. Other neoplastic lesions included gonadoblastoma (16% prevalence) and testicular carcinoma in situ (25.5%). In younger patients FSH serum levels were increased in 81% of cases (mean 2.82 ± 2.18 IU/L), while LH in 58% (mean 1.82 ± 1.69 IU/L). Hypergonadotropic hypogonadism was diagnosed in most of the pubertal/ /adult patients (mean FSH 54.2 ± 23.3 IU/L, mean LH 21.7 ± 12.1 IU/L, mean testosterone 5.5 ± 4.5 nmol/L). Dysgenetic gonads in patients with Y chromosome have a high risk of germ cell neoplasia (ca. 50%). If they are preserved until puberty/early adulthood, they may develop overt, invasive GCT. The gonads also have poor hormonal activity (hypergonadotropic hypogonadism) in most of the pubertal/adult patients. Each of these cases must be considered individually and a decision to remove the gonad or not should be based on the comprehensive analysis of the phenotype by a multidisciplinary team of specialists in consultation with the patient and the parents. If dysgenetic gonads are not resected in childhood, these patients need careful ongoing follow-up examination, including biopsy and histopathological evaluation.

Is a CIS phenotype apparent in children with Disorders of Sex Development? Milder testicular dysgenesis is associated with a higher risk of malignancy.

All malignant testicular germ cell tumors (TGCT) of adult men are preceded by an in situ stage (CIS) of protracted evolution. The adult CIS is well characterized, but there is debate on the phenotype of infantile CIS, its distinction from delayed maturation of germ cells and prognostic potential. A large series of 43 patients with Disorders of Sex Development (DSD) and dysgenetic testes (90% ranging from neonates to 12years, mean age 4.7years), was studied by quantifying dysgenetic features, degree of germ cell abnormalities/atypia (GCA), expression of OCT 3/4 (a pluripotency-undifferentiation marker), germ cell ploidy and evolution to CIS and invasive TGCT. Findings were compared with those of normal testes. The type of gonads present defined three groups of patients: bilateral testes (BT-DSD, n=21), one testis and one streak gonad (CT-DSD, C for combined, n=13), and ovarian-testicular combinations (OT-DSD, n=9). There were 5 boys with infantile CIS, bilateral in 3 (total of 8 infantile CIS) and two patients with adult CIS, bilateral in one (total of 3 adult CIS). Two patients had bilateral seminomas one at 12-17 and the other at 23years. Histological dysgenesis was significantly higher in CT-DSD (p<0.05), that had only 1 CIS. The highest frequency of GCA was in BT-DSD (p<0.05), which coincided with a total of 11CIS+Seminomas. In all patients, aneuploidy was significantly higher (63%) than diploidy (p<0.02), and GCA were more frequent in aneuploid than in diploid samples (p<0.02). All CIS and TGCT were OCT 3/4 positive. Finally, there was a significant association between the triad Aneuploidy+GCA+OCT 3/4 positivity and the incidence of CIS (Fisher Exact test p<0.002, relative risk 7.0). The degree of testicular dysgenesis (derived from abnormal organization of Sertoli cells in fetal testicular cords) is inversely related to the incidence of CIS. Our data demonstrate that the combined use of OCT 3/4 expression, quantification of germ cell abnormalities-atypia and ploidy in dysgenetic testes can satisfactorily identify infantile CIS with high risk of malignant evolution and set it aside from delayed germ cell maturation with lower or nil neoplastic potential.

Screening of Y chromosome microdeletions in 46,XY partial gonadal dysgenesis and in patients with a 45,X/46,XY karyotype or its variants

BackgroundPartial and mixed gonadal dysgenesis (PGD and MGD) are characterized by genital ambiguity and the finding of either a streak gonad and a dysgenetic testis or two dysgenetic testes. The karyotype in PGD is 46,XY, whereas a 45,X/46,XY mosaicism or its variants (more than two lineages and/or structural abnormalities of the Y chromosome) is generally found in MGD. Such mosaics are also compatible with female phenotype and Turner syndrome, ovotesticular disorder of sex development, and infertility in men with normal external genitalia. During the last few years, evidences of a linkage between Y microdeletions and 45,X mosaicism have been reported. There are also indications that the instability caused by such deletions might be more significant in germ cells. The aim of this work was to investigate the presence of Y chromosome microdeletions in individuals with PGD and in those with 45,X/46,XY mosaicism or its variants and variable phenotypes.MethodsOur sample comprised 13 individuals with PGD and 15 with mosaicism, most of them with a MGD phenotype (n = 11). Thirty-six sequence tagged sites (STS) spanning the male specific region (MSY) on the Y chromosome (Yp, centromere and Yq) were analyzed by multiplex PCR and some individual reactions.ResultsAll STS showed positive amplifications in the PGD group. Conversely, in the group with mosaicism, six individuals with MGD had been identified with Yq microdeletions, two of them without structural abnormalities of the Y chromosome by routine cytogenetic analysis. The deleted STSs were located within AZFb and AZFc (Azoospermia Factor) regions, which harbor several genes responsible for spermatogenesis.ConclusionsAbsence of deletions in individuals with PGD does not confirm the hypothesis that instability of the Y chromosome in the gonads could be one of the causes of such condition. However, deletions identified in the second group indicate that mosaicism may be associated with Y chromosome abnormalities detectable only at the molecular level. If patients with mosaicism and Y microdeletions reared as males decide to undergo in vitro fertilization, Y chromosomes which tend to be unstable during cell division may be transmitted to offspring.

46 XY Gonodal Dysgenesis

XY disorder of sex development (46,XY DSD) is characterized by a 46,XY karyotype, ambiguous genitalia with mild to severe penoscrotal hypospadias ,dysgenetic testes, reduced to no sperm production, and mullerian structures that range from absent to presence of a fully developed uterus and fallopian tubes. 46,XY complete gonadal dysgenesis is characterized by a 46,XY karyo- type, normal female external genitalia, completely undeveloped streak gonads, no sperm production, and presence of normal mullerian structures and often not diagnosed until puberty when secondary sexual characteristics fail to develop. The diagnosis of 46,XY DSD and 46,XY gonodal dysgenesis relies on clinical findings, gonadal histology, chromosome analysis testing to detect changes in genes.Because of increased risk for gonadal tumors(most commonly dysgerminoma) abdominal streak gonads should be surgically removed . Typically, hormone replacement therapy (HRT) is required from puberty onward. Here we describe the clini- cal, endocrinological and molecular data of a patient with complete 46, XY gonadal dysgenesis.

Complete androgen insensitivity syndrome associated with bilateral sertoli cell adenomas and paratesticular leiomyomas: Case report and review of the literature

BackgroundComplete androgen insensitivity syndrome (CAIS) is a rare and usually unexpected cause of primary amenorrhoea that results from receptor resistance to androgens, producing a female phenotype in genetically male patients. CaseA 16-year-old girl was diagnosed with CAIS after investigations for primary amenorrhoea. Her left inguinal gonad and the right intra-abdominal gonad were resected and histopathology revealed the presence of dysgenetic multinodular testes with absence of germ cells, significant hyperplasia of Sertoli cells (Sertoli cell adenoma) and presence of paratesticular leiomyomas. ConclusionAlthough the risk of gonadal tumour development is considered to be low, a variety of tumours have been described in association with CAIS, but this is the first report of development of bilateral paratesticular leiomyomas developing concurrently with Sertoli cell adenomas.

Dysgenetic male pseudohermaphroditism

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.

Clinical and gonadal features and early surgical management of 45,X/46,XY and 45,X/47,XYY chromosomal mosaicism presenting with genital anomalies

ObjectiveThe 45,X/46,XY and 45,X/47,XYY group of patients includes some of those previously diagnosed with ‘mixed gonadal dysgenesis’. Our aim was to establish the clinical and gonadal spectrum, and early surgical management, of patients with chromosomal mosaicism presenting with genital anomalies. Patients and methodsWe performed a retrospective review of patients with 45,X/46,XY or 45,X/47,XYY mosaicism presenting with genital ambiguity between 1988 and 2009. At least one gonadal biopsy or gonadectomy specimen was available for each patient. Gonadal histology was re-evaluated by a paediatric pathologist. ResultsOf 31 patients with 45,X/46,XY (n = 28) or 45,X/47,XYY (n = 3) mosaicism and genital anomalies, 19 (61%) were raised male. Histology of 46 gonads was available from patients who had undergone a gonadectomy or gonadal biopsy, at a median age of 9.5 months. 18 gonads were palpable at presentation, including 5 (28%) histologically unremarkable testes, 2 streak gonads, and 1 dysgenetic gonad with distinct areas of testicular and ovarian stroma but no oocytes. All intra-abdominal gonads were found to be dysgenetic testes (of which 2 were noted to have pre-malignant changes) or streaks, apart from 1 histologically unremarkable testis. 15 (48%) patients had other anomalies, most commonly cardiac and renal; 4 (13%) had a Turner phenotype. ConclusionThe anatomy and gonadal histology of 45,X/46,XY and 45,X/47,XYY individuals with genital ambiguity do not conform to a set pattern, and hence management of each patient should be individualized according to detailed anatomical and histological assessment.

An unusual case of ambiguous genitalia

Introduction: Mixed gonadal dysgenesis is most commonly associated with a mosaic 45X/46XY karyotype. The clinical phenotype may range from almost complete female or male external genitalia to ambiguous genitalia. The internal genitalia may be composed of dysgenetic testis on one side and a streak gonad on the contralateral side, however there can be varying configurations as well. The uterus and fallopian tubes are generally ipsilateral to the streak gonad and these retained Mullerian remnants are common. The presence of 45X may present with Turner like features including cardiac, renal anomalies and short stature. Case Report: We describe a case of ambiguous genitalia secondary to mixed gonadal dysgenesis where the sex assignment was made before the final diagnosis was reached. Conclusion: The diagnosis of mixed gonadal dysgenesis can be difficult for families. A multidisciplinary approach must be established for the patient and family while incorporating the psychosocial aspects also.

45,X/46,XY mosaicisme: Report of five cases and clinical review

Introduction The mosaicism 45, X/46, XY is a gonosomal abnormality characterized by a broad phenotypic spectrum, ranging from women with or without Turner syndrome stigmata, to men apparently normal, passing by the ambiguous phenotypes with variable virilisation of external genitalia. From the histological point of view, several situations may arise. Patients and methods We analyzed the clinical, hormonal, sonographic, and genitographics data, as well as peroperative and histological findings for five cases of mosaicism 45, X/46, XY, and we discussed treatment performed. Results The mean age of patients was 6.6 years, two had a female phenotype with clitoral hypertrophy (one of them had Turner syndrome stigmata), one had a normal male phenotype with bilateral cryptorchidism and two had an ambiguity of external genitalia assigned to male. Short stature was noted for four patients. Surgical exploration concluded to the diagnosis of mixed gonadal dysgenesis for four of our patients. No cases of gonadoblastoma have been reported, for girls a prophylactic gonadectomy was performed, for boys the streak gonad was resected and the dysgenetic testis biopsied and preserved, subject for constant monitoring. Conclusion This heterogeneity indicate the importance of an accurate clinical and histological evaluation of any patient presenting with 45, X/46,XY mosaicism.