45,X/46,XY Mosaicism with Male Phenotype: Case Report.

Mixed gonadal dysgenesis is the most common chromosomal abnormality with ambiguous genitalia, defined as a 45,X/46,XY mosaicism. It can present with a normal male phenotype, ambiguous genitalia, or features of Turner syndrome. A 14-year-old patient was referred to the genetics clinic due to hypospadia, cryptorchidism, and aortic coarctation. During the physical examination, short stature, webbed neck, and Blashko lines on his back were noted. He had a previous karyotype reported as normal. However, due to an inadequate evolution and a low resolution on the previous test, a higher resolution karyotype was performed, identifying a mosaicism 45,X/46,XY. A multidisciplinary board examined the case, and follow-up with tumor markers was carried out to evaluate the presence of gonadoblastoma, one of the main complications in these patients. Treatment should be transdisciplinary and focused on the particular characteristics of each case. Other treatment alternatives include corrective surgery and hormonal therapy.

Successful surgical sperm retrieval from a patient with 45,X/46,XY mosaicism followed by in vitro fertilization pregnancy: A case report.

RATIONALE: Mixed gonadal dysgenesis is a rare disorder of sex development, and typically contains a mosaic 45,X/46,XY karyotype. PATIENT CONCERNS: We reported here a case of a 42-year-old man with infertility for 6 years and inability to ejaculate during intercourse. DIAGNOSIS: Physical examination confirmed that the external genitalia was male. The right testis of this patient was resected and the left testis had intrascrotal calcification. Hormone test showed that the level of follicle-stimulating hormone was 20.14 IU/L (normal range, 1.27-19.26 IU/L). No deletion or mutation was found on the sex-determining region Y. H&E staining revealed seminiferous tubule dysgenesis. The karyotyping in peripheral blood and testicular tissue was 45,X/46,XY and 45,X/47,XYY/46,XY, respectively. Based on these results, the patient was diagnosed with 45,X/46,XY or 45,X/47,XYY/46,XY mosaicism and gonadal dysgenesis. INTERVENTIONS: In vitro fertilization and embryo transfer technology were used to help his wife to achieve pregnancy. OUTCOMES: A normal baby boy was born at 36 weeks of gestation with a karyotype 46, XY. LESSONS: We reported a rare case of a karyotype 45,X/46,XY in blood cells and 45,X/47, XYY/46,XY in testicular tissue. In vitro fertilization and embryo transfer technology can help to achieve pregnancy.

A Case of 45,X/46,XY Mosaicism Presenting as Swyer Syndrome.

BACKGROUND: Swyer syndrome is a difference of sex development that is typically associated with mutations in genes responsible for testicular development. It is speculated that some cases may result from cryptic 45,X/46,XY mosaicism leading to abnormal gonadal development. The presence or absence of a 45,X lineage is important for prognosis and management. CASE: We present a case of apparent Swyer syndrome associated with a 46,XY chromosomal complement in lymphocytes and 45,X/46,XY mosaicism on analysis of her noncancerous gonad. Gonadal histology was consistent with a 45,X phenotype. SUMMARY AND CONCLUSION: This case demonstrates the clinical variability in the presentation of 45,X/46,XY mosaicism and highlights the importance of thorough genetic testing that includes consideration of chromosomal mosaicism. We will discuss the implications of this diagnosis for management.

Clinical management in mixed gonadal dysgenesis with chromosomal mosaicism: Considerations in newborns and adolescents.

Individuals born on the spectrum of genetic abnormalities known as mixed gonadal dysgenesis (MGD) have a wide range of anatomical findings and management can be challenging in the newborn and adolescent. Historically, many individuals with MGD have undergone gonadectomy to avert the risk of gonadal malignancy. However, gonadectomy deprives patients of the benefits of their endogenous hormones, potential fertility, and in the case with MGD, has historically been done prior to addressing gender identity. Some patient advocates have proposed a delayed approach to surgical reconstructions and/or gonadectomy in other differences/disorders of sex development (DSD), particularly in patients with congenital adrenal hyperplasia and androgen insensitivity syndrome. In many areas of the world, there continues to be a shift toward delayed reconstructions and hesitancy regarding irreversible gonadectomy. To date, no clinical management protocol addressing these issues from a patient-centered approach has been described. We review what is known about malignancy risk and propose a management protocol for those with MGD that involves shared decision making regarding the gonads and addresses the long-term challenges with regard to gender and anatomy.

Neonato con genitales ambiguos: ¿disgenesia gonadal mixta? / Ambiguous genitalia in newborn: Mixed gonadal dysgenesis?

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Early Bilateral Gonadoblastoma Associated With 45,X/46,XY Mosaicism: The Spectrum of Undifferentiated Gonadal Tissue and Gonadoblastoma in the First Months of Life.

45,X/46,XY mosaicism is one of a heterogenous group of congenital conditions known as differences (disorders) of sex development (DSD) that results in abnormal development of internal and external genitalia. Patients with DSD, particularly those with segments of the Y chromosome, are at increased risk for germ cell tumors including gonadoblastoma. Gonadoblastoma is a neoplasm comprised of a mixture of germ cells and elements resembling immature granulosa or Sertoli cells with or without Leydig cells or lutein-type cells in an ovarian type stroma. Gonadoblastoma has an increased prevalence of 15% to 40% in patients with 45,X/46,XY mosaicism and has been previously reported in patients as young as 5 months of age with that karyotype. Herein, we describe a 3-month-old child with 45,X/46,XY karyotype who was referred for the evaluation of asymmetric labia majora. Additional evaluation revealed left streak gonad and right dysplastic/dysgenetic testis. Both gonads contained foci of cells typical for gonadoblastoma as well as undifferentiated gonadal tissue, underscoring the potential for very early infantile gonadoblastoma and the spectrum of developmental anomalies associated with this karyotype.

The Dilemma of Sex of Rearing: A Case of a 45,X/46,XY Neonate with Hydrocolpos.

BACKGROUND: A rare disorder of sex development is 45,X/46,XY mosaicism, which is phenotypically very heterogenous, ranging from normal male (or female) to that of genital ambiguity of varying degrees. CASE: We report a case of a neonate with 45,X/46,XY mosaicism and hydrocolpos, and we point out the dilemma and the difficulty in gender assignment. SUMMARY AND CONCLUSION: Gender assignment of cases with frank genital ambiguity is often difficult to be determined, because several factors have to be taken into consideration, such as genital appearance, anticipated urological and sexual function, capacity for future fertility, gonadal malignancy risk, and psychosocial factors. A multidisciplinary approach is definitely needed in the management of such cases.

The Evaluation of Cases with Y-Chromosome Gonadal Dysgenesis: Clinical Experience over 18 Years.

OBJECTIVE: Y-chromosome gonadal dysgenesis (GD) is a rare subgroup of disorders of sexual development (DSD) which results from underdeveloped testis and may exhibit heterogenous symptoms. These patients are phenotypically classified into two groups - complete and partial, and their karyotypic description is either 46,XY GD or 45,X/46,XY GD. In this study; we aimed to evaluate the characteristics of cases with Y-chromosome GD. METHODS: Thirty eight cases were followed-up between 1998 and 2016. The age of admission ranged between 0 and 17 years. Clinical and laboratory findings as well as follow-up characteristics of the cases were evaluated retrospectively from the patient files. RESULTS: There were 26 cases (four complete, 22 partial) in the 46,XY GD group, and 12 cases (four complete, 8 patients with complete GD in the 45,X/46,XY. Mean age at admission was 6.2±4.6 years for all cases. Patients with complete GD in the 45,X/46,XY GD group were diagnosed earlier that the patients with complete GD in the 46,XY group [11 years vs. 14.31 years of age (p<0.01)]. There were no additional findings in 55% of all patients. In the remaining 45% additional clinical findings, mainly short stature, were detected in 75% of the patients in the 45,X/46,XY GD and 30% of the patients in the 46,XY GD groups. All patients with complete 46,XY and 45,X/46,XY GD were raised as females. There was no gender dysphoria in patients that were raised as females, except for one case. Gonadectomy was performed in 14 patients, at a mean age of 8.75±2.3 years and pathological assessment of the gonads was reported as normal in all cases. CONCLUSION: Y-chromosome GD is a very heterogenous clinical and genetic disorder and requires a multifaceted approach to management. Whether including syndromic features or not, associated clinical features may lead to earlier diagnosis, especially in complete forms of GD. Due to difficulties encountered in the long-term follow-up of these patients, evaluation of appropriateness of sex of rearing decision is not truly possible. Performance of gonadectomy during the first decade appears be a preventive factor for tumor development since these tumors are usually seen during the second decade.

A Case of Chromosomal Disorders of Sex Development with Transverse Testicular Ectopia Mimicking Mixed Gonadal Dysgenesis.

Transverse testicular ectopia (TTE) is a rare form of ectopic testis observed in boys with a normal 46, XY karyotype. TTE can be associated with persistent Müllerian duct syndrome or other genital anomalies such as hypospadias. However, TTE concomitant with both persistent Müllerian duct remnants and hypospadias has never been reported in the literature. A case of chromosomal disorders of sex development with TTE and persistent Müllerian duct remnants, which was initially presumed to represent mixed gonadal dysgenesis, is presented.

Mixed gonadal dysgenesis in Yaoundé: A preliminary experience about three cases.

UNLABELLED: Mixed gonadal dysgenesis is characterised by unilateral chromosomal abnormality, which is probably the result of anaphase lag during mitosis. The 45, XO/46, XY karyotype is the most common form of mosaicism involving the Y chromosome. It is a rare clinical entity with a worldwide incidence of 1.5/10,000 live births. Its epidemiology in Sub-Saharan Africa is not known. This study reports experience in the management of 3 cases at the Yaounde Gynecologic-Obstetric and Paediatric Hospital. From November 2009 to November 2014, 3 cases were successfully managed at our institution. RESULTS: All patients presented with asymmetrical gonadal differentiation. On one side of the body, a poorly-developed testicular gonad and on the other side a gonadal streak. A persistent Mόllerian remnant was equally found in the 3 cases. Management of mixed gonadal dysgenesis should be done in tertiary health care centres. A multidisciplinary team approach is recommended.

[Clinical and genetic analysis for a patient with 45, X/46, X, Yqh- and mixed gonadal dysgenesis].

OBJECTIVE: To investigate the clinical and genetic characteristics of a patient with mixed gonadal dysgenesis. METHODS: Clinical data was collected. The patient was subjected for serum hormone testing and G-banding chromosomal analysis. Sex-determining region of Y-chromosome (SRY) gene and azoospermia factor (AZF) a, b, c regions were analyzed with multiple polymerase chain reaction (PCR) and whole gene sequencing. RESULTS: All serum hormone testing were normal. The karyotype of the patient was 45,X/46,X,Yqh-. PCR has proven the presence of SRY, ZFY and AZFa, and deletion of AZFb and AZFc regions. No mutation was detected in the sequence of the SRY gene. Abdominal computerized tomography has detected a huge mass in the pelvic cavity, which was positive for PLAP and CD117 on immunohistochemistry stain. CONCLUSION: Based on clinical data and result of genetic testing, the patient was diagnosed with mixed gonadal dysgenesis. Pathological and immunohistochemistry analysis of the transformed gland has confirmed the diagnosis of seminoma. For patient with a karyotype of 45,X/46,X,Yqh-, the risk of seminoma may be related with the presence of SRY gene.

Disgenesia gonadal mixta como forma de presentación de un desorden de la diferenciación sexual de causa cromosómica / Mixed gonadal dysgenesis as a form of presentation of sex differentiation disorder of chromosomal origin

La diferenciación sexual es un proceso genéticamente determinado y controlado, que puede ser alterado por diferentes tipos de mutaciones genéticas, o por el efecto de hormonas u otros disruptores ambientales que actúan sobre el embrión, resultando en la formación de genitales externos que no se corresponden con el sexo genético y con los genitales internos. La disgenesia gonadal mixta clasifica en los desórdenes de la diferenciación sexual de causa cromosómica. Se describe un paciente de un año de edad que es atendido en el Hospital Pediátrico “Juan Manuel Márquez”, por presentar genitales externos atípicos. El diagnóstico del paciente fue de disgenesia gonadal mixta, y se realizó con los complementarios siguientes: ecografía ginecológica, estudios hormonales y cariotipo. El tratamiento instaurado inicialmente, fue quirúrgico en dos tiempos operatorios, y el seguimiento hormonal hasta la pubertad (14 años), cuando se inició terapia de reemplazo hormonal según lo establecido por la edad de la paciente.

Sex differentiation is a genetically determined and controlled process that may be altered by various types of genetic mutations or by the effect of hormones or other environmental disruptors acting upon the embryo. The result is the formation of external genitalia that does not match with the genetic sex and the internal genitalia. Mixed gonadal dysgenesis is classified into the sexual differentiation disorders of chromosomal cause. Here is a one-year old child, who was seen at “Juan Manuel Marquez” pediatric hospital since he presented with atypical external genitalia. The diagnosis was mixed gonadal dysgenesis, based on supplementary tests like gynecological echography, hormone studies and karyotype. The initial treatment was surgical in two surgical times, and the hormonal follow-up lasted till puberty (14 years) when the hormone replacement therapy started according to the indications for the patient's age.

Disgenesia gonadal mixta como forma de presentación de un desorden de la diferenciación sexual de causa cromosómica / Mixed gonadal dysgenesis as a form of presentation of sex differentiation disorder of chromosomal origin

La diferenciación sexual es un proceso genéticamente determinado y controlado, que puede ser alterado por diferentes tipos de mutaciones genéticas, o por el efecto de hormonas u otros disruptores ambientales que actúan sobre el embrión, resultando en la formación de genitales externos que no se corresponden con el sexo genético y con los genitales internos. La disgenesia gonadal mixta clasifica en los desórdenes de la diferenciación sexual de causa cromosómica. Se describe un paciente de un año de edad que es atendido en el Hospital Pediátrico Juan Manuel Márquez, por presentar genitales externos atípicos. El diagnóstico del paciente fue de disgenesia gonadal mixta, y se realizó con los complementarios siguientes: ecografía ginecológica, estudios hormonales y cariotipo. El tratamiento instaurado inicialmente, fue quirúrgico en dos tiempos operatorios, y el seguimiento hormonal hasta la pubertad (14 años), cuando se inició terapia de reemplazo hormonal según lo establecido por la edad de la paciente(AU)

Sex differentiation is a genetically determined and controlled process that may be altered by various types of genetic mutations or by the effect of hormones or other environmental disruptors acting upon the embryo. The result is the formation of external genitalia that does not match with the genetic sex and the internal genitalia. Mixed gonadal dysgenesis is classified into the sexual differentiation disorders of chromosomal cause. Here is a one-year old child, who was seen at Juan Manuel Marquez pediatric hospital since he presented with atypical external genitalia. The diagnosis was mixed gonadal dysgenesis, based on supplementary tests like gynecological echography, hormone studies and karyotype. The initial treatment was surgical in two surgical times, and the hormonal follow-up lasted till puberty (14 years) when the hormone replacement therapy started according to the indications for the patient's age(AU)

[The diagnosis, treatment and following up of 7 patients with 45, X/46, XY mixed gonadal dysgenesis].

OBJECTIVE: To investigate the clinical features, therapeutic regimens and follow-up information of patients with 45, X/46, XY mixed gonadal dysgenesis in order to improve the diagnosis and treatment of the disease. METHODS: We performed a retrospective review of patients with 45, X/46, XY mosaicism hospitalized in Chinese PLA General Hospital between 2000 and 2014. The clinical features,sex hormones,treatment and follow-up information were summarized. RESULTS: (1) Seven patients ranging 12-17 years old were diagnosed as having 45, X/46, XY mixed gonadal dysgenesis. Six of them had female sex of rearing and one had male. (2) All of them presented with short stature and growth retardation, and had similar specific somatic signs to Turner syndrome. (3) The external genitalia presented with a wide variety of phenotypes. One patient presented with male phenotype with hypospadia, one presented with clitoridauxe, and five presented with female phenotype. The masculinization scores for the external genitalia showed that five patients presented with female phenotype, one patient with mild undervirilization and one patient with ambiguous genitalia. (4) By surgical exploration and ultrasound, two patients were found with testes and one was with ovary-like gonads. No gonad could be detected in the other four patients. (5) Five patients were treated with recombinant human growth hormone (rhGH). Two patients received sex hormone replacement therapy with one patient taking testosterone, whose penis became enlarged and erect after treatment, and one taking artificial cycle. CONCLUSIONS: The patients with 45, X/46, XY mosaicism share similar specific somatic signs to Turner syndrome. The 45, X/46, XY mosaicism presents with a wide spectrum of phenotypes with the highest proportion of being genital ambiguity. RhGH, testosterone and artificial cycle can be used accordingly.

Ovotesticular disorder of sexual development due to 47,XYY/46,XY/45,X mixed gonadal dysgenesis in a phenotypic male presenting as cyclical haematuria: clinical presentation and assessment of long-term outcomes.

Ovotesticular disorder of sexual differentiation (OTDSD) is a rare cause of disorder of sexual differentiation predominantly having 46,XX karyotype, female phenotype and ambiguous genitalia. We report a 15-year-old having male body habitus, axillary and pubic hair, well-developed penis and right-descended testis with history of penoscrotal hypospadias correction, presenting with three episodes of cyclical haematuria, who biochemically had normal serum testosterone (338 ng dl(-1) ) which increased following hCG stimulation (614 ng dl(-1) ), elevated estradiol (17.35 pg ml(-1) ) along with elevated luteinising hormone (11.3 mIU l(-1) ) and follicle-stimulating hormone (31 mIU l(-1) ). Ultrasonography followed by micturating cystourethrogram and cystoscopy confirmed the presence of prostate, uterus, cervix and vagina draining into the urogenital sinus continuing till the penile urethra and left intra-abdominal gonad. Patient underwent hysterectomy and left gonadectomy. Histopathologic study of resected gonad confirmed presence of ovotestis. Low estradiol (1.2 pg ml(-1) ) following gonadectomy confirmed the ovotestis origin of estradiol. Chromosomal analysis revealed complex karyotype predominant being 47,XYY (50%) followed by 46,XY (26%) and 45,X (24%). This is perhaps the first report of 47,XYY/46,XY/45,X causing OTDSD in a phenotypic male.

Mixed gonadal dysgenesis in a patient with de novo tas(Y;19)(p11.3;q13.4) and 45,X mosaicism.

We report a patient with a de novo telomeric association between chromosomes 19 and Y in conjunction with mixed gonadal dysgenesis. The patient was first admitted to the clinic because of abnormal external genitalia. Laparoscopic evaluation revealed (1) a rudimentary uterus, one fallopian tube, and a small gonad resembling an ovary on the right side, and (2) an immature fallopian tube, a vas deferens, and a gonad resembling a testis on the left side. Conventional cytogenetic analysis performed on cultivated peripheral blood cells, and tissue obtained from the phallus and a gonadal structure which resembled a testis revealed two different cell lines with the 46,X,tas (Y;19)(p11.3;q13.4) and 45,X karyotype. Y chromosome microdeletion analysis showed that the patient did not have any genomic deletions in the AZFa, b, c, or SRY regions on the long arm of the Y chromosome. This is the first report of a patient with mixed gonadal dysgenesis that is accompanied by a telomeric association between chromosomes 19 and Y with 45,X mosaicism.

The use of fluorescence in situ hybridization in the diagnosis of hidden mosaicism: apropos of three cases of sex chromosome anomalies / O uso da hibridação in situ com fluorescência no diagnóstico de mosaicismo oculto: a propósito de três casos de anomalias de cromossomos sexuais

FISH has been used as a complement to classical cytogenetics in the detection of mosaicism in sex chromosome anomalies. The aim of this study is to describe three cases in which the final diagnosis could only be achieved by FISH. Case 1 was an 8-year-old 46,XY girl with normal female genitalia referred to our service because of short stature. FISH analysis of lymphocytes with probes for the X and Y centromeres identified a 45,X/46,X,idic(Y) constitution, and established the diagnosis of Turner syndrome. Case 2 was a 21-month-old 46,XY boy with genital ambiguity (penile hypospadias, right testis, and left streak gonad). FISH analysis of lymphocytes and buccal smear identified a 45,X/46,XY karyotype, leading to diagnosis of mixed gonadal dysgenesis. Case 3 was a 47,XYY 19-year-old boy with delayed neuromotor development, learning disabilities, psychological problems, tall stature, small testes, elevated gonadotropins, and azoospermia. FISH analysis of lymphocytes and buccal smear identified a 47,XYY/48,XXYY constitution. Cases 1 and 2 illustrate the phenotypic variability of the 45,X/46,XY mosaicism, and the importance of detection of the 45,X cell line for proper management and follow-up. In case 3, abnormal gonadal function could be explained by the 48,XXYY cell line. The use of FISH in clinical practice is particularly relevant when classical cytogenetic analysis yields normal or uncertain results in patients with features of sex chromosome aneuploidy. Arq Bras Endocrinol Metab. 2012;56(8):545-51.

FISH tem sido usado como um complemento para a citogenética clássica na detecção de mosaicismo em anomalias de cromossomos sexuais. O objetivo deste trabalho é descrever três casos nos quais o diagnóstico final só foi obtido por meio de FISH. O caso 1 é uma menina de 8 anos, 46,XY, com genitália feminina normal, encaminhada ao nosso setor devido à baixa estatura. A análise de linfócitos por FISH com sondas centroméricas de X e Y identificou a constituição 45,X/46,X,idic(Y) e estabeleceu o diagnóstico de síndrome de Turner. O caso 2 é um menino de 21 meses, 46,XY, com ambiguidade genital (hipospadia peniana, testículo à direita e gônada disgenética à esquerda). FISH de linfócitos e mucosa oral identificou o cariótipo 45,X/46,XY, levando ao diagnóstico de disgenesia gonadal mista. O caso 3 é um rapaz de 19 anos, 47,XYY, com atraso de desenvolvimento neuromotor, dificuldade de aprendizado, problemas psicológicos, alta estatura, testículos pequenos, gonadotrofinas elevadas e azoospermia. FISH de linfócitos e mucosa oral identificou a constituição 47,XYY/48,XXYY. Os casos 1 e 2 ilustram a variabilidade fenotípica do mosaico 45,X/46,XY e a importância da detecção da linhagem 45,X na avaliação e na condução dos casos. No caso 3, a função gonadal anormal pôde ser explicada pela linhagem 48,XXYY. O uso de FISH na prática clínica é particularmente relevante quando a análise citogenética clássica traz resultados normais ou incertos em pacientes com quadro sugestivo de uma aneuploidia de cromossomos sexuais. Arq Bras Endocrinol Metab. 2012;56(8):545-51.

Müllerian remnant malignancy.

Mixed gonadal dysgenesis is a disorder of sexual differentiation, characterized by mosaicism, ambiguous external genitalia, and both Wolffian and Müllerian internal genitalia. These patients are at a known increased risk of germ cell cancer, specifically gonadoblastoma; however, in this report we describe a case of adenocarcinoma of a remnant Müllerian structure.