Histopathological spectrum of disorders of sexual development: a case series of seven cases

Disorders of sexual development (DSD) refer to cases in which there is a discordance among at least two of the following; genetic sex, gonadal sex, genital tract sex and phenotypic sex. DSDs are quite rare with reported incidence varying from 1 in 4,500 to 1 in 5,500. Ovotesticular disorder is amongst the rarest variety of DSD comprising only to 3-10% of all cases of DSD with only 500 cases reported till now worldwide. Frequency of MRKH syndrome is 1 in 4,500 cases and is the cause of amenorrhoea in 15% of cases of primary amenorrhoea. Authors present a case series of seven cases of DSDs with three cases diagnosed as androgen insensitivity syndrome, two cases of true ovotesticular DSD (true hermaphrodite), one case each of mixed gonadal dysgenesis and Mayer-Rokitansky-Kuster Hauser (MRKH) syndrome. Authors received the histopathology specimen of these cases in this department which was extensively sampled to study the gonads and the other derivatives of Mullerian and Wolffian duct and to rule out presence of any malignancy.

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 / Mixed gonad dysgenesis

La Disgenesia Gonadal Mixta (DGM); es un desorden de la diferenciación sexual (DDS) caracterizado por presencia de tejido testicular inmaduro ò disgenètico de un lado y estría gonadal contralateral, con frecuencia asociado a un mosaico cromosómico tipo 45 X / 46XY. Representa la segunda causa de genitales ambiguos en neonatos después de la hiperplasia suprarrenal congénita y se caracteriza por presentar talla baja y estigmas turnerianos en la infancia y amenorrea primaria en la adolescencia. Se debe diagnosticar tempranamente ya que frecuentemente se asocia a malignización de las gónadas en relación a la presencia de un cromosoma “Y” en alguna de las líneas celulares de la persona afectada. Se reporta el caso de una lactante de 11 meses de edad referida a la consulta de ginecología infanto juvenil del Instituto Docente de Urología en Valencia estado Carabobo por presentar genitales ambiguos desde el nacimiento. Se describen las características al examen físico y el enfoque clínico y terapéutico, haciendo énfasis en los métodos diagnósticos de laboratorio, los hallazgos a la laparoscopia y de la biopsia gonadal. Encontrándose a la evaluación laparoscópica: útero central, testículo derecho y estría gonadal izquierda, la biopsia gonadal reportó presencia de túbulos seminíferos prepuberales y el cariotipo gonadal (método de hibridación fluorescente in situ ò método de FISH) reportó cariotipo 45X/46XY, realizándose posteriormente la gonadectomìa bilateral y la clitoroplastia reductora. Se concluye, la DGM representa una emergencia médica y social debido a la presencia de genitales ambiguos al nacer y el riesgo de malignización futura de las gónadas y su manejo clínico y terapéutico deben ser siempre interdisciplinarios.

The Mixed Gonadal Dysgenesis (MGD) is a disorder of sex development characterized for presence of immature or dysgenetic testicular tissue and contralateral streak gonad frequently associated to chromosome mosaic type 45X/46XY and genital ambiguity. This condition represents the second cause of ambiguous genitalia in neonates after congenital adrenal hyperplasia; characterized by short stature, turner`s stigmata in infancy and primary amenorrhea in adolescence. It should be diagnosed early due to risk of malignant transformation of gonads by the presence of Y chromosome in cell lines of the affected patiens. We report the case of a female infant of 11 motnhs old referred to gynecological pediatric consult of the Instituto Docente de Urologia in Valencia, Carabobo showing genital ambiguity since birth. Characteristics from the physical examination, clinical and therapeutic approach, with emphasis on the laboratory diagnostic methods, laparoscopy finding and gonadal biopsy are described. The laparoscopy evaluation revealed central uterus, right testicle and left gonadal streak. The gonadal biopsy reported the presence of prepuberal seminiferous tubules and the gonadal karyotype (FISH method) reported 45X/46XY; subsequently deciding bilateral gonadectomy and clitoroplasty. In conclusion, MGD represents a social and medical emergency due to the presence of ambiguous genitalia and the risk of future malignant transformation of the gonads. The clinical and therapeutic management should always be interdisciplinary.

Mixed gonadal dysgenesis in 45,X Turner syndrome with SRY gene

Turner syndrome is the most common chromosomal disorder in girls. Various phenotypic features show depending upon karyotype from normal female through ambiguous genitalia to male. Usually, Turner girls containing 45,X/46,XY mosaicism, or sex-determining region Y (SRY) gene may have mixed gonadal dysgenesis with various external sexual differentiation. We experienced a short statured 45,X Turner girl with normal external genitalia. Because SRY gene was positive, laparoscopic gonadectomy was performed. The dysgenetic gonads revealed bilateral ovotesticular tissues. The authors report a mixed gonadal dysgenesis case found in clinical 45,X Turner patient with positive SRY gene. Screening for SRY gene should be done even the karyotype is 45,X monosomy and external genitalia is normal.

Mixed gonadal dysgenesis with normal karyotype : A rare case report.

Mixed gonadal dysgenesis (MGD) presents as a unilateral testis, usually intraabdominal, a streak gonad on contralateral side, and persistent mullerian structures. 45X/45XY karyotype is most frequent in such cases with predominance of 45X cells in both peripheral lymphocytes and gonads. We present a rare case of a left undescended testis, normally descended right testis, with penoscrotal hypospadias, who had a normal karyotype and whose histopathological findings were endometrial tissue and fallopian tube in left testicular biopsy. Gonadal dysgenesis should always be kept a possibility in patient with undescended testis and proximal hypospadias. If karyotype reveals a 46XY gonadal dysgenesis, these patients need all the more careful follow-up to screen for gonadoblastoma in remaining normal testis. Subjecting the patients to prophylactic orchidectomy with hormone replacement can be an additional option in such patients.

Mixed Gonadal Dysgenesis Mimicking True Hermaphroditism

A differential diagnosis between the true hermaphroditism (TH) and mixed gonadal dysgenesis (MGD) has important clinical implications for gender assignment and the decision for early gonadectomy; however, variable clinical and histological features frequently lead to the confusion of TH with MGD. A 17- month-old boy was presented with proximal hypospadias with chordee and right non-palpable testis in his scrotum. He also had right auricular anomaly including a separated tragus with skin tag. Left testis was well palpable in his left scrotum. Diagnostic right inguinal exploration showed Mullerian structures such as a gonad like an ovary and a fallopian tube with a uterus, which were removed. Repair of hypospadias and right auricular anomaly was also done. Following ultrasonography (USG) showed a normal looking testis in left scrotum. His chromosome was 45, XO/46, XY. We report a difficult case of mixed gonadal dysgenesis mimicking true hermaphroditism which combines ipsilateral congenital auricular anomaly.

A Cytogenetic Study in Patients with Sex Chromosome Abnormalities / 소아과

PURPOSE: This study was performed to evaluate the recent frequency of karyotypes in different sex chromosome abnormalities and to evaluate the age and clinical manifestations at diagnosis. METHODS: Peripheral blood leukocytes were obtained from subjects who were clinically suspected to have sex chromosome abnormalities and referred to the cytogenetic laboratory in the Department of Pediatrics, Kyungpook National University Hospital from February 1981 to August 2001. RESULTS: The relative frequencies of different sex chromosome abnormalities were Klinefelter (52 percent), Turner (42 percent), XXX syndrome (3 percent) and mixed gonadal dysgenesis (3 percent). The populations of different karyotypes in Klinefelter syndrome were 47, XXY (97 percent) and 46, XY/ 47, XYY (3 percent). The populations of different karyotypes in Turner syndrome were 45, X (67 percent, ), mosaicism (23 percent), and structural aberrations (10 percent). The populations of different karyotypes in XXX syndrome were 47, XXX (67 percent, ) and 46, XX/47, XXX (33 percent). All mixed gonadal dysgenesis were 45, X/46, XY. Eighty one percent of sex chromosome abnormalities was diagnosed after puberty. Patients diagnosed with Klinefelter and Turner syndrome in infancy showed nearly normal phenotypes or had minor congenital malformations. CONCLUSION: Early diagnoses of sex chromosome abnormalities is required to prevent associated morbidities and to maximize growth and development. We have to pay careful attention in diagnoses of Turner syndrome because of the high proportion of mosaicism and structural aberrations.

A case of gonadoblastoma in patient with mixed gonadal dysgenesis / 대한산부인과학회잡지

Gonadoblastoma occurs almost always in association with a Y chromosome cell line, and developes in one third of patients with Mixed gonadal dysgenesis. Removing of gonads of intersex patients with the Y chromosome is very important because of the strong association of the genesis of tumor in dysgenetic gonads with the presence of a Y chromosome. But it is always possible that an XY cell line could be missed, or that a fragment from Y chromosome could have been translocated and not discovered by chromosomal analysis. PCR with Y specific probe or Southern blotting would reveal the presence of a Y or a translocated fragment. We experienced an 18-year-old woman represent with primary amenorrhea who had 45,X/46,X,+mar. Y-specific PCR revealed that the marker chromosome was drived from Y chromosome. After both gonadectomy and clitorial recession, we found the gonadoblastoma in dysgenetic testis. So we report it with brief review of literatures.

Critical Histopathologic Findings for Differential Diagnosis between True Hermaphroditism and Mixed Gonadal Dysgenesis / 대한비뇨기과학회지

PURPOSE: Differentiation of true hermaphroditism (TH), from mixed gonadal dysgenesis (MGD), in patients presenting with ambiguous genitalia and asymmetric gonad, is mandatory. However, clinical features, including chromosomal, hormonal, biochemical and radiological findings are not helpful in the differential diagnosis between these conditions, so histopathological diagnosis of the gonads is essential. We reviewed the clinicopathological features of TH and MGD to investigate the important histopathological criteria for the differential diagnosis. MATERIALS AND METHODS: The medical records of 38 patients with ambiguous genitalia were retrospectively reviewed. 8 patients had been diagnosed as TH or MGD, so their histological slides were reevaluated. We also studied the normal gonadal histology for the prenatal period in order to get basic knowledge on the histological features of premature testis and ovaries in infancy. RESULTS: To make a clear diagnosis between TH and MGD, the histological features of the ovarian compartment are important. The well-formed primordial, primary or mature follicles, with primary oocytes in TH, were distinguishable from the primitive germ cells in the ovarian-type stroma and primitive sex-cord like structures in MGD. On the contrary, the testicular compartment under both conditions was not critical for the differential diagnosis. A streaky gonadal portion should be examined to avoid missing the diagnosis of a streak-testis. CONCLUSIONS: The differential diagnosis between TH and MGD depends on the interpretation of the histological features of the gonads. For the purpose of a differential diagnosis, we have to understand the normal gonadal histology at the infantile period, and apply strict criteria to the gonads, such as testis, ovary, streak gonad and streak-testis through examination of the entire tissue.

Clinical Characteristics in the 45XO/46XY Mosaicism and 45XO with SRY Gene Positive Patients / 대한비뇨기과학회지

PURPOSE: We investigated the clinical characteristics and relationship between chromosome and its phenotypic expression in patients with 45 XO/46XY mosaicism or 45 XO with SRY gene. MATERIALS AND METHODS: 11 patients with 45XO/46XY chromosomal abnormality and 4 patients with 45XO with SRY positive reaction admitted from 1990 to 1996 were evaluated. Patients were grouped according to chromosome and gonadal expression. Group A consisted of patients with 45XO/46XY chromosome and unilateral streak gonad, group B patients with 45XO chromosome, SRY positive reaction and unilateral streak gonad and group C patients with 45XO/46XY chromosome and bilateral streak gonads. RESULTS: Of the total 15 patients, the number of patients in group A, B, and C were 8, 4, and 3, respectively. SRY gene was positive in all group A and B patients but only one patient was positive in group C. Of the 8 patients in group A, 5 patients had a high XY mosaicism ratio compared to XO whereas an equal ratio was observed in the remaining 3 patients. Of the 4 male penotype patients only 1 patient had a high XY mosaicism ratio compared to XO while 3 patients displayed an equal ratio. There was no difference in associated anomaly and the degree of severity of ambiguity according to the mosaicism ratio in all patients. CONCLUSIONS: There was no definite correlation between the mosaicism ratio and phenotypic expression. Presence of SRY gene in 45XO patients may suggest MGD(mixed gonadal dysgenesis) and therefore, the evaluation SRY gene could be useful in the diagnosis of 45XO patients with ambiguous genitalia.

A case of Mixed Gonadal Dysgenesis Managed in Newborn Period / 대한비뇨기과학회지

The authors have experienced a case of mixed gonadal dysgenesis who had a testis on the left side and a streak gonad on the right side with a karyotype of 45,XO/46,XY mosaicism. Bilateral gonadectomy and feminizing genitoplasty were performed for this neonate.

A Case of Mixed Gonadal Dysgenesis With 45X/46XY Karyotype and Patent Ductus Arteriosus / 대한비뇨기과학회지

Mixed gonadal dysgenesis (MGD) with 45X/XY karyotype and patent ductus arteriosus (PDA) is a rare congenital abnormality. A thirty eight month-old male patient was admitted to our urology department for evaluation of ambiguous genitalia. On physical examination, a ptosis, a wide neck with a low posterior hairline, small phallus, testis in the right labioscrotal fold, urethral opening on the penoscrotal junction, and typical findings of patent ductus arteriosus were present. The chromosome karyotype of the patient was 45X/XY. On the laparotomy there were infantile fallopian tubes, ovary and a immature testis on the left. The treatment of the patien1 included gender identity. excision of mullerian structure, left gonadectomy, urethroplasty, biopsy of right testis and double ligation of PDA. We report a case of mixed gonadal dysgenesis with 45X/XY karyotype and patent ductus arteriosus.