Pediatric and Developmental Pathology 18, 345–352, 2015 DOI: 10.2350/14-04-1466-PB.1 ª 2015 Society for Pediatric Pathology
PERSPECTIVES IN PEDIATRIC PATHOLOGY
Perspectives in Pediatric Pathology, Chapter 7. Ovotesticular DSD (True Hermaphroditism) MANUEL NISTAL,1 RICARDO PANIAGUA,2 PILAR GONZA´LEZ-PERAMATO,1
AND
MIGUEL REYES-MU´GICA3*
1
Pathology, Hospital La Paz, Universidad Auto´noma de Madrid, Calle Arzobispo Morcillo #2, Madrid 28029, Spain Department of Cell Biology, Universidad de Alcala, Madrid, Spain 3 Department of Pathology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA 2
Received April 19, 2014; accepted May 20, 2014; published online August 8, 2014.
INTRODUCTION Formerly known as “true hermaphroditism,” ovotesticular disorders of sex development (Ovotesticular DSD) are anomalies resulting from abnormal gonadal differentiation, characterized by the presence of testicular and ovarian parenchyma in the same individual. These disorders occur in less than 10 percent of the population with DSD [1–3], with an incidence of 1/100 000 live births [4]. By 1991, approximately 500 cases had appeared in the literature [5]. The diagnosis of “true hermaphroditism” presents difficulties because these patients show a variable phenotype. The age at diagnosis ranges from the newborn period to 60 years [6], but only 25% of patients are diagnosed before 20 years of age. Not infrequently, these patients have multiple surgical repairs of hypospadias or cryptorchidism before arriving at the correct diagnosis [7,8].
KARYOTYPE AND PATHOGENETIC THEORIES The most frequent karyotype of patients with Ovotesticular DSD is 46, XX (60%), followed by chromosomal mosaicisms, which, in decreasing order of frequency, include 46, XX/46, XY; 46, XY/47, XXY; 45, X0/46, XY; 46, XX/45, X0; 46, XX/47, XXY (33%), and finally 46, XY karyotype (7%). Isolated cases with karyotypes 47, XYY/46, XY/45, X0 [9] and 46, XderY/45, X0 with rearranged Y chromosome [10] have been reported. These figures do not express the actual distribution of karyotypes around the world. While most African patients (96.6%) show a 46, XX karyotype, chromosomal mosaicism is found in 40.5% of cases in Europe, and only in 21% of cases in North America. The 46, XY karyotype is rare, and its frequency is similar in Europe, Asia, and North America [11,12]. *Corresponding author, e-mail:
[email protected] Most Ovotesticular DSD are sporadic. When several occur in one family, 46, XX males without “hermaphroditism” are frequently found in the same family. This finding supports the notion that both anomalies are alternative phenotypes of the same genetic defect [13,14], probably an autosomal dominant mutation with incomplete penetrance, or an X-linked mutation [15,16]. Pathogenetic theories explaining Ovotesticular DSD start from the premise that if the patient has testes, the testicular determining factor (TDF) produced by the SRY gene is present. This is easy to explain when the karyotype is 46, XY, mosaicism 46, XX/45, XY, or chimera 46, XY. Finding testicular parenchyma in a patient with a 46, XX karyotype (the most common situation) is more difficult to understand and has been explained by four pathogenetic mechanisms: (1) a hidden mosaicism, including a cell line carrying the Y chromosome [17]; (2) translocation of paternal Y chromosomal material that includes the SRY gene to the X chromosome; (3) an autosomal mutation with variable penetrance; and (4) by X-linked chromosome mutations either coupled with a rare X chromosome inactivation [18], allowing testicular differentiation in the absence of SRY [19], or mutations in genes, such as SOX9 and FGF9, that regulate the action of SRY [20]. Other causes are partial deletion of DMRT1 (deletion of 35 Kb affecting exons 3 and 4 of the DMRT1 gene) [21] and mutations in RSPO1 [22]. Molecular studies have revealed that only a few 46, XX patients with Ovotesticular DSD show Y-DNA chromosome sequences [13]. This is in contrast with the so-called XX males (46, XX testicular DSD) who show Y chromosome material, including TDF in 80% of cases [23]. Some 46, XX patients with Ovotesticular DSD (“true hermaphrodites”) who are SRY-negative in lymphocyte studies show SRY in DNA obtained from the testicular parenchyma of the ovotestis [24–26].
Figures 7.1–7.8. Figure 7.1. External male genitalia are hypoplastic with a penile clitoris, hypoplastic labia, and vaginal vestibule. Figure 7.2. Ovotestes in a child. The ovarian parenchyma forms a cap over the testicle attached to it by a pedicle. Figure 7.3. Ovotestis in a child. A gonad with two parts separated by a connective septum. The upper zone shows ovarian parenchyma overlying testicular parenchyma. Among some seminiferous tubules, primordial follicles can be identified. Figure 7.4. Ovotestis in a child. Numerous primordial follicles without maturation set in abundant spindle cell stroma. Figure 7.5. Ovotestis in a child. Testicular parenchyma with richly-cellular stroma similar to ovarian stroma. Some seminiferous tubules are markedly hypoplastic. The more developed ones show some germ cells. Figure 7.6. Ovotestis in a child. Epithelial cords with irregular shape and microliths. Underneath the surface, these cords are embedded in ovarianlike stroma. Figure 7.7. Cross-section of a uterine tube close to tubular structures that resemble epididymis. Figure 7.8. Ovotestis in an adult. Several sections of the same gonad show solid areas that correspond to testicular parenchyma, and cystic ovarian follicles in different stages of maturation. A color version of this figure is available online.
PHENOTYPE The phenotype of these patients is related to the presence of the SRY gene and varies from female to normal male (Fig. 7.1), but those with male phenotype do not exceed
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10% [27,28]. In XX patients the phenotype depends on two features, the length of translocated Y material and whether the SRY gene is translocated to the active X chromosome. Longer Yp fragments result in more
Figures 7.9–7.14. Figure 7.9. Ovotestis in an adult. Low power field shows several developing ovarian follicles surrounding testicular parenchyma. The testicular tissue is adjacent to a corpus albicans. Figure 7.10. Ovotestis in an adult. A group of seminiferous tubules are embedded in an abundant stroma containing several corpora albicantia. Figure 7.11. Ovotestis in an adult. Seminiferous tubules surrounding a luteal body on the right. Figure 7.12. Ovotestis in an 18-year-old patient showing seminiferous tubules with no lumen. They are lined by Sertoli cells with hyperchromatic nuclei (prepubertal maturation). The interstitium shows Leydig cell hyperplasia. Figure 7.13. Ovotestis of an adult. Marked variation is noted in shape and size of seminiferous tubules with prepubertal maturation. The interstitium contains numerous Leydig cells. Figure 7.14. Ovotestis in an adult showing Sertoli-only cell and completely hyalinized seminiferous tubules. A color version of this figure is available online.
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complete masculinization, and with the translocated SRY gene the phenotype will be an XX male with virilized external genitalia. If the translocation involves the inactive (through lyonization) X chromosome, the phenotype will feature ambiguous genitalia. Most patients seek medical attention for the first time at puberty. Phenotypical males complain of breast development (95% Ovotesticular DSD patients show some degree of gynecomastia) [29], periodical hematuria (when there is a functional uterus opening into the urinary tract) [30], or cryptorchidism [31]. A 46, XX patient with complete male phenotype and no evidence of SRY, absent female internal genitalia, and presence of prostate has been reported [32]. Patients with female phenotype present with menstrual disorders or clitoromegaly, and more rarely with cyclic pain in a descended or undescended gonad [33]. Some isolated cases seek medical help for an irreducible hernia that encloses a small uterus (hernia uteri inguinalis), and a phenotype similar to type 1 persistent mu¨llerian duct syndrome, but obviously with a different type of gonad [34]. True hermaphroditism should be suspected in infants showing sexual ambiguity [35].
TYPES OF GONADS The types of gonads observed in Ovotesticular DSD patients are: ovotestis (44%), ovary (33%), and testis (22%). Depending on the type and laterality of the abnormal gonad, Ovotesticular DSD is classified into three types: unilateral, bilateral, and lateral. Most cases are of the unilateral type, with ovotestis on one side and a normal gonad on the other side. In 40% of patients there is an ovotestis and a contralateral ovary, and in 15% an ovotestis and a testicle. In the bilateral type, which accounts for 34%, both gonads are ovotestes. The remaining 11% of patients fall into the lateral type of Ovotesticular DSD, where one gonad is testis and the other gonad is ovary [32,36–38]. Other rare presentations include an ovotestis and a contralateral streak gonad [39,40], and patients with crossed ectopy consisting of a left side ovotestis displaced to the right scrotum [41]. Patients with a Y chromosome have a testis more frequently than those without it (55.8% vs. 22.7%). The degree of gonadal descent is directly proportional to the amount of testicular tissue present. The nature of the gonad can be suspected on clinical examination. High serum testosterone levels suggest the presence of Leydig cells, and ,therefore, the presence of a testis. High levels of E2 after human menopausal gonadotropin (hMG) stimulation suggest the presence of an ovary [42]. Ovotestis The ovotestis is the most frequent gonadal type found in Ovotesticular DSD patients (44.4%). It is predominantly on the right side, abdominal in half of the cases, and inguinal, scrotal, or labial in the other half. Only 5% of
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patients with bilateral ovotestes show complete gonadal descent [43,44]. Macroscopically, ovotestes can be bilobed or ovoid. If bilobed, testicular and ovarian tissues are joined by a pedicle. If ovoid, the ovarian tissue forms a cap on the testicular parenchyma (Fig. 7.2). The limits between testicular and ovarian parenchyma may be welldefined in some cases, while in others the oocytes are spread among seminiferous cords/tubules, or even inside the tubules (Figs. 7.3,7.4). The ovarian/testicular proportion of tissue varies widely from one patient to another. The testicular zone neighboring the ovarian component shows significant changes in interstitium and tunica albuginea. The interstitial tissue has ovarian-like stroma, not the characteristic loose connective tissue of a normal testis (Fig. 7.5). The tunica albuginea covering the testicular zone shows poor differentiation with persistence of tubular structures within it or that cross it to reach the mesothelial surface. The mesothelial lining of this zone can be columnar instead of flattened. These findings are similar to those observed in male patients with persistence of mu¨llerian structures (“pseudohermaphrodites”) [10] (Fig. 7.6). In a large series of Ovotesticular DSD in South African patients, three different types of ovotestes were observed and were divided by their gross appearance into bipolar (11%) and mixed (89%) types. Histologically, bipolar ovotestes had a strictly polarized distribution of ovarian and testicular tissue, with an irregularly interdigitating junction between them. Mixed ovotestes had an outer mantle of ovarian tissue encasing an inner core with two distinct patterns. In almost half (44%), the central core consisted of gonadal stroma with scattered foci of separate ovarian and testicular tissue. The remaining 56% showed a compartmentalized ovotestis in which the outer mantle was thickened in the upper pole and which surrounded a large core of testicular tissue in the lower pole. Statistical analysis showed no correlation between the type of gonadal tissue and the clinical or genital features [38]. The ovotestis is associated with a fallopian tube in 65% of cases, and with a vas deferens in the remainder (Fig. 7.7). A uterus is completely developed in patients with ovotestis/ovary. When ovotestis is bilateral, uterine agenesis is found in 13% of cases [37]. Microcystic transformation of ductuli efferentes is observed frequently in the epididymis accompanying the ductus deferens. In adults, several degrees of follicular maturation, corpora lutea or corpora albicantia can be observed (Figs. 7.8–7.11). The seminiferous tubules rarely develop spermatogenesis, often show a Sertoli-only, dysgenetic appearance (Figs. 7.12,7.13), and frequently undergo hyalinization (Fig. 7.14). Sertoli cells in adults are positive with inhibin immunostaining and maintain the expression of D2-40, which is indicative of immaturity (Figs. 7.15–7.17). Many Sertoli cells are negative for androgen receptor (Fig. 7.18). The interstitium features numerous Leydig cells (Fig. 7.12).
Figures 7.15–7.20. Figure 7.15. Inhibin immunostaining in an ovotestis. The amount of testicular parenchyma in ovotestes can be scarce. Seminiferous tubules are highlighted by inhibin staining, also expressed in the ovarian follicle in maturation. Figure 7.16. Ovotestis in an adult. Inhibin immunostaining is positive in seminiferous tubules and Leydig cells. Seminiferous tubules are immature and malformed. Figure 7.17. Ovotestis in an adult. D240 immunostaining is positive in immature and malformed seminiferous tubules. The perifollicular stroma also is positive. Figure 7.18. Ovotestis in an adult. Androgen receptor staining is scarcely expressed in Sertoli cells or even absent in some seminiferous tubules. This contrasts with strong expression in peritubular and interstitial cells. Figure 7.19. Prepubertal testis in a true hermaphrodite. Seminiferous tubules show a high number of Sertoli cells. Many tubules are devoid of germ cells. Figure 7.20. Ovary in a prepubertal true hermaphrodite. Follicles are in several developmental stages. A color version of this figure is available online.
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Testis The testis is preferentially located on the right side (60%) at any level from the abdomen to the scrotal pouch or labia. From infancy, the testis shows a low tubular fertility index (Fig. 7.19). At puberty, the seminiferous tubules do not reach a normal diameter and often consist only of dysgenetic Sertoli cells, similar to those observed in many cryptorchid testes. Incomplete spermatogenesis can be observed in some cases, but complete spermatogenesis is exceptional. Although some testicular lesions may be primary, others could be due to the increased level of estrogens to which the testicular parenchyma is exposed. Ovary The ovary is found most frequently on the left side (63%), and in the abdomen. In most instances, the ovary is hypoplastic and shows scanty primordial follicles. In a few patients the ovary is histologically and functionally normal (Fig. 7.20). Shimoda and colleagues reported an atypical patient with a 45X/46X,dic(Y) karyotype featuring an ovary with the appearance of a streak gonad and a contralateral ovotestis [45]. More than two dozen pregnancies in patients with Ovotesticular DSD have been reported [46–54]. This is in contrast with the exceptional cases of paternity [55]. The origin of oocytes might be an ovotestis [56] or an ovary [57]. Most patients develop hypergonadotropic hypogonadism.
TREATMENT OF OVOTESTICULAR DSD The treatment of ovotesticular DSD is complex because it requires experts in several subspecialized fields. These include experts in genetic sex, gonadal sex, social sex, and psychological sex. The patients relatives also should be involved in the decision-making process and treatment [34,58]. In addition, there are three main treatmentdetermining elements: the patient’s age at the time of diagnosis, nature and location of gonads, and development of external genitalia [59]. Genetic sex determined by karyotype and/or Y chromosome sequencing is not considered a determining criterion [60]. Although bilateral castration might be justified to stave-off the risk of gonadal neoplasia, gonadal preservation offers some advantages. This may be important if the patient is growing as a girl who may have a spontaneous puberty, and even be fertile. The incidence of tumors has been estimated between 4% for those with 46, XX karyotype, and 10% when the karyotype is 46, XY or with a mosaicism 46, XX/XY [11,61]. The most frequent tumors seen in this context are gonadoblastoma, dysgerminoma/seminoma [62–65], choriocarcinoma [66], and yolk sac tumor. Other reported neoplasms are mature teratoma, carcinoid [67], and granulosa cell tumor [68]. Tumors in these gonads, like those of cryptorchid testes, can reach great sizes before their diagnosis. The risk of tumor can be minimized if the following precautions are
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taken: removal of a testis that cannot be descended to the scrotum, and periodical survey of the residual gonad by ultrasonography. Very close follow-up is necessary if the patient has a chromosomal mosaicism. Another important fact to take into account is the high frequency of a gonadal tumor developing in many of these patients after longterm follow-up.
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