In two patients, bilateral gonadectomies were performed because these two patients were clinically diagnosed as having MGD. In the remaining two cases, normal-appearing gonads were not removed.
In one case, a unilateral gonadectomy with a biopsy on the opposite gonad was performed; and in the other case, only a unilateral gonadectomy was performed because the opposite gonad appeared radiologically and grossly normal. The ages of the six patients with MGD at the time of gonadectomy or biopsy ranged from 1 to 24 months mean, A bilateral gonadectomy was performed in three patients, and a unilateral gonadectomy with a biopsy of the contralateral normal-appearing gonads in the remaining three patients.
The latter three patients are undergoing close clinical follow-ups for gonadal tumors by ultrasonography. Of four cases of TH, two cases were classified as unilateral type and the other two as lateral according to the location of the gonadal tissue 4. In two cases having unilateral ovotestis, the ovarian and testicular tissue were arranged in an end-to-end fashion. Histological features of gonadal tissue were similar in all cases of TH.
The testicular compartment showed numerous solid seminiferous tubules filled with immature Sertoli cells and a few primitive germ cells.
The immature Sertoli cells had a regular, round to ovoid nucleus with inconspicuous nucleoli. The germ cells were found adjacent to the basement membrane and those were distinguishable from the immature Sertoli cells because of their larger nuclei and abundant cytoplasm. In three cases Cases 2—4 , the tubules were compact with scanty amount of interstitium Fig.
The interstitium contained undifferentiated spindle cells, but mature Leydig cells were not identified in any case. In the ovarian compartment, numerous primordial follicles and a few primary and antral follicles were found in the condensed outer cortex Fig.
In the primordial follicles, a single layer of flattened follicular cells pregranulosa cells surrounded the oocytes. Case 3. Ovotestis in true hermaphrodite. A, testicular compartment shows solid tubules filled with immature Sertoli cells and germ cells arrow.
B, ovarian compartment has numerous primordial and growing follicles containing primary oocytes within the ovarian cortical stroma. C, primordial follicles are invested by a single layer of flattened follicular cells arrow , and each contains a primary oocyte.
In all six cases of MGD, the histological features of the differentiated gonad testis were indistinguishable from the testicular compartment in TH. Within the solid seminiferous tubules, germ cell components were contrasted with the immature Sertoli cells. As in cases of TH, the number of germ cells were low in the cases having compact tubules Cases 5, 9 , but the number was increased up to 10 per tubule in two cases with an edematous and abundant interstitium Cases 6 and 10; Fig.
In three cases Cases 5, 6, and 10 , psammomatous calcifications were noted in the center of the tubules. In two cases Cases 5 and 10 , the stroma of the peripheral portion of the differentiated testis imperceptibly merged into ovarian-type stroma, in which primitive germ cells and stromal cells were intimately admixed and formed primitive sex-cordlike structures Figs.
These features mimicked those of gonadoblastoma; however, the characteristic features of gonadoblastoma, such as cellular nests showing hyaline Call-Exner-like bodies or calcification, were not present. Mitotic figures were not seen in either germ cell or sex-cordlike components. In three cases Cases 6, 8, and 9 , the side contralateral to the differentiated gonads showed anastomosing trabeculae or cordlike structures composed of immature sex-cordlike elements.
Germ cell components were rare or absent in the cordlike structures in those cases; these findings were reminiscent of the granulosa cell or Sertoli cell tumors Fig. In one case Case 9 , germ cells were only rarely identified within the trabeculae, and these were intimately associated with lymphoid aggregates Fig. The contralateral gonad in one case Case 7 had streak tissue composed almost exclusively of ovarian-type stroma with rare foci of atrophic sex-cordlike structures composed of barely recognizable tubular or cordlike structures Fig.
Primordial or growing follicles were not identified in any cases of MGD. Case 5. Mixed gonadal dysgenesis. A, testicular compartment has histological features similar to those of true hermaphrodite; the number of germ cells arrow is increased in a case with abundant edematous interstitium compared with in the cases that have compact tubules.
B, the stroma of the differentiated testis imperceptibly merges into the adjacent dysgenetic gonadal tissue left half , where germ cell and stromal cell components form primitive cordlike structures in the ovarian-type stroma; primordial or growing follicles are not identified. Sex-cordlike components in mixed gonadal dysgenesis. A, trabeculae or cordlike structures consisting of an intimate mixture of primitive germ cells and stromal cells mimic features of gonadoblastoma Case 5.
B, sex-cordlike structures composed only of stromal cells are reminiscent of those in adult granulosa cell tumor or Sertoli cell tumor Case 6. C, only a few germ cells arrow are identified in the sex-cordlike structures, and these are associated with many scattered lymphoid aggregates.
D, streak gonad is almost exclusively composed of ovarian-type stroma and rare foci of atrophic sex-cordlike structures arrow. First, a bilateral gonadectomy is recommended as soon as possible in all individuals with MGD containing Y-chromosome material. In TH, however, only the removal of the opposite gonad from the assigned gender and a biopsy of remaining gonadal tissue for histological evaluation may be appropriate.
Second, gender assignment is critical for the treatment of patients of TH because these patients usually do not possess any other developmental malformations, and thus normal sexual and reproductive functions can be achieved by proper management and sex assignment at a young age 4. In contrast, it is important that bilateral gonadectomies be performed in patients with MGD before the patient reaches puberty, not only to prevent the development of malignant tumors but also to avoid virilization if the patient is to be raised as female.
In the three patients with MGD in our study, however, contralateral differentiated gonads have been preserved under close clinical follow-up until the patients' puberty so that they can be raised as male. Third, certain medical problems, such as deficient immunoglobulin levels, aberrant bony development of inner ear structures, and cardiovascular and renal anomalies, are more common in MGD patients than in TH patients; therefore, patients with MGD should receive more medical attention 1 , 3.
For a differential diagnosis, chromosomal constitutions are not helpful. The pathogenesis of TH and MGD still remains unclear, but recent study shows that sex determination is not from a simple hierarchical cascade of gene action but from a complex network of gene expression and protein-protein interaction in which SRY, SOX9, WT1, and SF1 are involved 13 , In cases of 46,XX true hermaphroditism, mosaicism with a Y-bearing cell line at low level 15 or partial inactivation of the Y-bearing X chromosome that was formed during paternal meiosis 16 , 17 have been suggested to explain the mechanism of abnormal sexual development.
In cases of MGD, mutations in SRY genes were usually absent 18 ; however the cytogenetic mosaicism, mutation in the genes downstream of SRY, and unpaired or incompletely paired X chromosome have been proposed as a mechanism to cause defective formation of the follicular mantle and degeneration of oocytes Approximately , primordial follicles, each containing a primary oocyte, are embedded in the stroma of the normal ovarian cortex at birth, and oogonia or primordial germ cells are usually absent 20 , Therefore, the presence of numerous primordial follicles containing primary oocytes with or without maturing follicles is considered well-developed ovarian tissue when making a definitive diagnosis of TH after birth and the finding of rare primordial follicles is insufficient to call it ovarian tissue.
More mature follicular structures, such as primary or antral follicle, can be identified, but those are not absolutely required for the diagnosis of TH. Primitive sex-cordlike structures with many primordial germ cells after birth should not be confused with well-developed ovarian tissue, even if they are embedded in the ovarian-type stroma.
It is noteworthy that five of six cases with MGD in our study showed either gonadoblastoma-like or sex-cord stromal tumor-like areas. Numerous germ cell components were intimately admixed with sex-cordlike elements in the former, whereas most of the germ cell components were eliminated in the latter.
Scattered lymphoid aggregates with a rare germ cell component within the ovarian-type stroma in a case Case 9 raised the possibility of an immune mechanism involved in the degenerative process forming a streak gonad.
The number of primordial germ cells varies depending on the age of the patient at the time of histological diagnosis, and virtually none are detectable at the time of puberty 2. Therefore, we thought that the germ cells migrated to the genital ridge and that then, accelerated atresia of primordial germ cells and sex-cord stromal cells occurred to form streak gonad during the prenatal or early postnatal period.
Gonadoblastoma was named as such because it appeared to recapitulate gonadal development more completely than any other type of tumor However, the size of the gonadoblastoma-like or granulosa cell tumor-like areas in our cases was too small to diagnose as such, and they did not exhibit mitotic activity.
Furthermore, those structures showed sequential changes of degeneration of the germ cells and sex-cord stromal cells in the ovarian-type stroma Fig. On the other hand, secretion of the testicular hormone is inhibited by the negative feedback effect of ovarian steroids through the inhibition of gonadotropin 4. In our study, the testicular compartments of patients with TH were those of normal prepubertal immature testes and were indistinguishable from those of patients with MGD Fig.
Paradoxically, breast development was typical at puberty, even with predominantly male external genitalia. This may have reflected atrophy of testicular tissue due to intraabdominal location. As noted, gonads may consist of two ovotestes; one ovary and one contralateral testis; or one ovotestis and a contralateral ovary or testis. Gonadal tissue may be located in the ovarian, inguinal, or labioscrotal regions. A testis or an ovotestis is more likely to be present on the right than on the left.
Spermatozoa are rarely present; 1 however, ostensibly normal oocytes may exist even in ovotestes. Gonads were palpable in only 59 of the South African cases of Wiersma et al. In 66 cases, gonads were in the pelvis. Ovotestes are the predominant gonadal form in South Africa and these were almost always pelvic in location.
In the series of Wiersma tissue distribution was typically bipolar ovarian cranial and testicular caudal , albeit with interdigitation. The clinical significance of gonadal intermingling is that extirpating gonadal tissue of a single type is not simple surgically.
Van Niekerk, whose elegant book in analyzed a presumably different South African cohort, reported at the time that the greater the proportion of testicular tissue in an ovotestis, the greater the likelihood of gonadal descent.
Van Niekerk collected cases from the region surrounding Pretoria, whereas Wiersma 19 , 20 is active in Durban. Thus, different tribal ancestry may exist. Van Niekerk noted that ovotestis may be detectable by inspection or palpation; testicular tissue is softer and darker than ovarian tissue. Ultrasound or magnetic resonance imaging MRI are now obligatory if the undesired portion of an ovotestis is to be extirpated. Gonadal neoplasia and breast carcinoma have been reported. The preponderance of gonads existing in the form of ovotestes in South Africa is less pronounced elsewhere.
Absence of a uterine horn usually indicates ipsilateral testis or ovotestis. The fimbriated end of the fallopian tube is often occluded ipsilateral to an ovotestis. Squamous metaplasia of the endocervix may occur.
Presence of a uterus in true hermaphroditism is diagnostically useful, particularly in the rare 46,XY case. Menstruation occurred in three of seven pubertal individuals with a uterus. A fallopian tube is invariably present ipsilateral to an ovary, whereas a vas deferens, epididymis, and, often, a seminal vesicle are usually present: ipsilateral to a testis. Either fallopian tubes or Wolffian derivatives may be present on the side of an ovotestis, although most often a fallopian tube is present.
Although fallopian tubes and Wolffian derivatives are usually not both present on the same side, even on the side of an ovotestis, this combination has been observed occasionally. The karyotype can be explained readily by postulating loss of certain cell lines and retention of others.
The possibility of chimerism has not been excluded, however, or even, in most cases, vigorously pursued. Of 13 cases detected up to , most were studied by cultured lymphocytes. The sex of rearing was chosen by the attending physicians in ten cases.
The gonadal distribution shows no obvious pattern Table 1. A uterus was present in eight of ten cases, two being unicornuate. Prevalences of bicornuate and unicornuate uteri seem likely to be underestimated, since the uterus was often not completely described.
This assumption, however, has not been proved and, in fact, often cannot be demonstrated, although one should recall that in gonadal cultures fibroblasts rather than germ cells are cultured. A male sex of rearing was chosen in five of the eight cases. A uterus was found in five cases. Five of eight had one ovary and one testis, and in four of these five, the testis was on the right. No case had bilateral ovotestes Table 1. These karyotypes probably arise by mitotic nondisjunction, although chimerism has not been excluded.
Because only a few cases have been associated with a given karyotype, generalizations would be unwise; however, alternating gonadal hermaphroditism occurs relatively frequently. About 40 cases of 46,XY true hermaphroditism have been reported, although a complete description is not available for all of them. Over half were Japanese; 46,XY true hermaphroditism appears to be the most common type of true hermaphroditism in Japan, in contrast to its relative rarity outside Asia. A sex of rearing was assigned in 19 cases, and in only two cases was the female role chosen.
Quantitation of genital virilization, however, is difficult. The gonadal distribution in Table 1 shows a high frequency of the alternating type, specifically a left ovary and a right testis.
No 46,XY true hermaphrodites definitely had bilateral ovotestes, although one possible case was reported by Sandberg et al. Breast carcinoma has also been reported in two true hermaphrodites; one was 46,XX 21 and the karyotype of the other 29 is unknown. Some 46,XY cases may also be unrecognized chimeras.
In 46,XX true hermaphrodites, possible explanations include translocation during paternal meiosis of SRY from the Y to an X; translocation of SRY from the Y to an autosome; or activation depression of autosomal genes. A few 46,XX ovotesticular cases do show a mutant SRY, and somatic mutation can result in gonadal mosaicism associated with true hermaphroditism. This hypothesis is supported by the existence of families characterized by either multiple siblings with XX true hermaphroditism or families in which both 46,XX males and 46,XX true hermaphrodites occur in the same kindred.
In these kindreds, the 46,XX men usually show genital ambiguity, unlike the typical 46,XX male who shows normal male external genitalia. Familial XX true hermaphrodites seem more likely to be characterized by bilateral ovotestes and absence of the uterus than nonfamilial true hermaphroditism; 2 both gonads in familial true hermaphroditism tend to be morphologically similar and ovotestes. This suggests a central basis for gonadal perturbation.
True hermaphroditism is a rare form of intersex anomaly where both male and female gonads are present. True hermaphrodites diagnosed in the past have been preferentially reared as males. However, based on the appearance of their external genitalia and the ability to reconstruct a functional genitourinary system, most of these children should be raised as girls. Between and , we managed eight children with true hermaphroditism.
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