Joe Leigh Simpson
Table Of Contents
Joe Leigh Simpson, MD
HISTORICAL BACKGROUND AND DEFINITIONS
TYPES OF TRUE HERMAPHRODITISM
True hermaphrodites have ovarian as well as testicular tissue. The diagnosis has traditionally been applied only if an individual has 1) histologically verified ovarian follicles or proof of their prior existence (e.g., corpora albicantia) and 2) seminiferous tubules or spermatozoa. Fibrous stroma does not suffice in lieu of follicles, nor do Leydig cells suffice in lieu of tubules. The diagnosis is applied regardless of chromosome complement. True hermaphroditism has been reported in humans and in many animals; in some lower animals, in fact, hermaphroditism is functional. This review will, however, be restricted to true hermaphroditism in humans. More extensive reviews are published elsewhere.1,2
|HISTORICAL BACKGROUND AND DEFINITIONS|
Klebs3 is usually credited with the first scientific consideration of true hermaphroditism. By the beginning of the modern cytogenetic era (circa 1958), approximately 200 true hermaphrodites had been documented. Analysis of these earlier cases led to certain clinical generalizations that still retain some validity. For example, most true hermaphrodites were raised as males, even though many had hypospadias and incomplete labioscrotal fusion. Gonads in these individuals consisted of either 1) bilateral ovotestes (so-called bilateral gonadal hermaphroditism), 2) one ovary and one testis (alternating gonadal hermaphroditism), or 3) one ovotestis and a contralateral testis or ovary (unilateral gonadal hermaphroditism). Ovarian and testicular portions of ovotestes usually were juxtaposed end-to-end, facilitating diagnosis by inspection or palpation. A uterus was usually present. A fallopian tube was usually present ipsilateral to an ovary and often ipsilateral to an ovotestis. If a testis was present, a vas deferens and epididymis were usually present ipsilateral to the testis. At puberty, breast development usually .occurred (Fig. 1) and menstruation often occurred.
By 1977, cytogenetic studies had been performed on at least 240 live-born cases that fulfilled traditional histologic criteria of hermaphroditism2. This group will serve as the basis for our clinical deductions.
Several potential cases that the reporting investigators had considered true hermaphrodites were excluded either because oocytes were not detected or because tubules were not present. The diagnosis was especially likely to be applied erroneously to 45,X/46,XY individuals. It is true that restricting the appellation true hermaphroditism only to cases in which both oocytes and tubules are present is arbitrary, in that oocytes may have been present during embryogenesis or neonatal life, only to undergo attrition thereafter. This would be analogous to the ontogenesis of streak gonads in 45,X individuals. A true hermaphrodite, if not ascertained until a later age, may no longer have detectable oocytes even though oocytes were present earlier. In such a case, the true nature of the disorder would not be appreciated, and the individual would not be identified as a true hermaphrodite. Even allowing for such unidentified cases, it is obvious that the disorder is rare.
|TYPES OF TRUE HERMAPHRODITISM|
About 30 cytogenetically documented 46,XX/46,XY true hermaphrodites have been reported. True hermaphroditism of the type 46,XX/46,XY is rarer than 46,XX true hermaphroditism but about as common as the 46,XY type. Not all 46,XX/46,XY individuals are true hermaphrodites; some are phenotypically normal or have gonadal dysgenesis or male pseudohermaphroditism. In fact, fusion of XX and XY mouse zygotes usually produces not true hermaphroditism but, rather, clearly male or clearly female offspring6.
A 46,XX/46,XY chromosome complement could arise by 1) nondisjunction involving a 47,XXY or 46,XY zygote, with loss of certain cell lines and retention of others, or 2) chimerism.
The etiology of 46,XX/46,XY true hermaphroditism in humans is usually suspected to be chimerism, rather than nondisjunction. Chimerism connotes the presence in a single individual of cells derived from different zygotes. The phenomenon is proved by detection of two populations of cells, usually erythrocytes with different blood types, in a single individual. At least three types of chimerism are known: 1) blood chimerism (interchange of blood cells between co-twins through placental anastomoses), 2) transplacental chimerism (interchange of fetal and maternal blood cells), and 3) whole-body chimerism. Whole-body chimerism, presumably the type of chimerism responsible for some 46,XX/46,XY true hermaphrodites, could result from 1) fertilization of both an ovum and its polar body, 2) fertilization of each of two ova contained within a single binucleated follicle, 3) fertilization of ova derived from different follicles, followed by fusion, or 4) other related phenomena. Whole-body chimerism can be assumed if two or more genotypes are 1) present in nonhematogenous tissues (skin or gonads) or 2) persist in hematogenous tissues. The frequency of whole-body chimerism may be underestimated, since chimeric individuals are usually ascertained because of abnormal sexual development (e.g., true hermaphroditism). Thus, almost all recognized whole-body chimeras are heterosexual, although one might expect an equal number of isosexual chimeras. That whole-body chimerism has been detected in phenotypically normal individuals confirms that a 46,XX/ 46,XY karyotype is not invariably associated with true hermaphroditism.
In any case, it is assumed that presence of ovarian as well as testicular tissue reflects products elaborated by the Y and not elaborated by the X--probably H-Y antigen. Indeed, Winters et al7 report that the testicular but not the ovarian portion of an ovotestis contains H-Y antigen.
Ascertainment of 46,XX/46,XY true hermaphrodites has been accomplished by studies restricted to lymphocytes as well as by studies of both lymphocytes and other tissues (e.g., skin or gonadal fibroblasts). In 3 cases, cytogenetic studies limited to lymphocytes would have failed to detect more than one line. If additional tissues are studied, the minority cell line is most likely to be detected in gonadal fibroblasts and relatively less likely to be detected in skin fibroblasts. In addition, the proportion of 46,XY cells in lymphocytes bears no ostensible relationship to gonadal status. That is, a relatively high proportion of 46,XY cells in lymphocytes does not necessarily indicate that the gonadal tissue is predominantly testicular, nor, conversely, does a high proportion of 46,XX cells indicate that gonadal tissue is predominantly ovarian. The clinical significance of these observations is that analysis of multiple tissues is the only way to detect certain 46,XX/46,XY true hermaphrodites, although many can be detected by analyzing lymphocytes alone.
The external genitalia of 46,XX/46,XY true hermaphrodites are usually either ambiguous or sufficiently masculinized to suggest to attending physicians that the sex of rearing should be male. A female sex of rearing was chosen in only 3 of 13 cases. Even if reared as males, affected individuals usually show perineal or penoscrotal hypospadias and incomplete labioscrotal fusion.
The distribution of gonadal tissue is shown in Table 1. No single type predominates. Although the chromosome constitution of gonadal tissue has been determined in only a few cases, 46,XY cells appear more likely to be present in a testis or ovotestis than in an ovary. Additional studies, however, are necessary to confirm this hypothesis. In aggregate, the right gonad is much more likely to contain testicular tissue than the left--a characteristic that 46,XX/46,XY true hermaphrodites share with other true hermaphrodites. There is no obvious explanation for the predilection for testicular development to take place on the right, but it is interesting to note that in many species, the right gonad is vestigial. Furthermore, following extirpation of the left ovary from newborn hens, the right gonad differentiates into a testis8.
O, ovary; T, testis; OT, ovotestis.
*Complete descriptions not available for all cases.
†Includes only those cases in which attending physicians assigned a sex of rearing.
‡Includes cases in which uterus described as rudimentary.
§Probably an underestimate; descriptions of uteri often incomplete.
||References 20–25; cases of Kasdan et al (28) and Berger et al (29) not included.
From Simpson JL: True hermaphroditism: Etiology and phenotypic considerations. Birth Defects 14(6C):9, 1978.
The ovarian and testicular portions of an ovotestis are usually juxtaposed end-to-end. By definition, both seminiferous tubules and ovarian follicles are present. Testicular tissue, whether existing as a separate testis or as one component of an ovotestis, is characterized by relatively few normal germ cells. The tubules are usually hyalinized and composed only of Sertoli cells (Fig. 2); Leydig cells may be hyperplastic. Although spermatozoa are rare, one possible 46,XX/46,XY case9 was fertile and had a sperm count of 20 × 106/ml. By contrast, ovarian tissue often contains numerous primordial follicles in various developmental stages. That ovarian tissue is often normal is also evidenced by breast development, cyclic menses, and histologic evidence of ovulation. However, histologic criteria for diagnosis introduce some biases favoring presence of normal oocytes in true hermaphrodites.
True hermaphrodites with 46,XX/46,XY karyotypes usually have müllerian derivatives, namely a uterus and one or more fallopian tubes. Rarely is the uterus absent, although a few authors comment that uterine development was rudimentary or “merely a remnant.” Menstruation occurred in 3 of 7 puberal individuals with a uterus. The presence or absence of fallopian tubes or wolffian derivatives reflects the ipsilateral gonad. 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, contrary to opinions stated by some authors. In 2 cases, gonadal tumors developed.
True hermaphroditism associated with a 46,XX/47,XXY chromosome complement probably results from nondisjunction involving a 46,XY or 47,XXY zygote. 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.
By 1977, 13 cases had been detected, usually on the basis of cultured lymphocytes. The sex of rearing was chosen by the attending physicians in 10 cases. The gonadal distribution shows no obvious pattern (Table 1). A uterus was present in 8 of 10 cases, 2 being unicornuate. Prevalences of bicornuate and unicornuate uteri seem likely to be underestimated, since the uterus was often not completely described. The occurrence of unicornuate or bicornuate uteri would be predicted because androgens and the müllerian inhibitory factor (MIF) influence embryonic ductal differentiation through local diffusion from the fetal testes.
Individuals with a 45,X/46,XY karyotype display a spectrum of phenotypes, ranging from almost normal males to females indistinguishable from those with 45,X gonadal dysgenesis and the Turner stigmata1. The different phenotypes presumably reflect different tissue distributions of 45,X and 46,XY cells. 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.
The phenotype most often associated with 45,X/46,XY mosaicism is mixed or asymmetric gonadal dysgenesis, characterized by a unilateral streak gonad and a contralateral testis. In most 45,X/46,XY individuals, no ovarian follicles are detectable, and hence the diagnosis of true hermaphroditism is inappropriate.
Although 11 45,X/46,XY true hermaphrodites have been reported, only 8 were completely described. A :male sex of rearing was chosen in 5 of the 8 cases. A uterus was found in 5 cases. Five of 8 had one ovary and one testis, and in 4 of these 5, the testis was on the right. No case had bilateral ovotestes (Table 1).
Other Forms of Mosaicism or Chimerism
True hermaphroditism has been associated with various other chromosomal abnormalities, including 45,X/46,XX; 46,XX/47,XYY; 46,XX/46,XY/ 47,XXY; 46,XX/47,XXY/49,XXYYY; 45,X/46,XY/ 47,XYY; and 46,XX/48,XXYY. 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 2 cases was the female role chosen. This indicates that the external genitalia are more masculine in appearance than in 46,XX/46,XY true hermaphroditism, a suggestion consistent with published descriptions of external genitalia. 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 1 possible case was reported by Sandberg et al10. A uterus was present in 17 of 19 cases for which complete descriptions were available; 2 uteri were unicornuate and 1 was bicornuate. Development of wolffian and müllerian derivatives was similar to that in other true hermaphrodites.
The presence of oocytes in 46,XY true hermaphrodites could result from 1) undetected chimerism or mosaicism, with 46,XX cells present but not readily detectable, 2) translocation of ovarian determinants from the X chromosome to either the Y chromosome or an autosome, or 3) a mutant gene or genes.
Certain phenotypic features in recent reviews1,2 suggest that undetected chimerism or mosaicism is often, although not necessarily always, the cause of 46,XY true hermaphroditism. For example, in one survey the frequency of alternating gonads was relatively high--16 of 28 cases (58%)2. Moreover, the gonadal tissue appeared more likely to be testicular than ovarian, and the external genitalia were relatively more virilized than in true hermaphrodites with other karyotypes. True hermaphrodites of type 46,XY were especially likely to differ from 46,XX true hermaphrodites with respect to gonadal distribution, extent of virilization, and sex of rearing. The differences observed would be expected if ostensible 46,XY cases actually had mosaicism or chimerism in which the proportion of 46,XX cells was relatively small and hence difficult to detect. That is, if some cells contained the factor responsible for the true hermaphroditism and others did not, dissimilar gonads might be expected. Few cytogenetic studies have been extensive enough to exclude mosaicism or chimerism in 46,XY true hermaphrodites.
By contrast, if 1) X-Y interchange, 2) a Y-autosome translocation, or 3) a mutant allele were present, both gonads would theoretically seem likely to be morphologically similar (i.e., bilateral ovotestes) because every cell would presumably possess the factor responsible for abnormal gonadal development. X-Y or Y-autosome translocations remain theoretic explanations for 46,XY true hermaphroditism, but no cytogenetic data support their existence. The relatively high frequency of 46,XY true hermaphroditism among Japanese suggests presence of a mutant gene, since differences in racial prevalences are often the first clue to an underlying genetic etiology. The lack of familial aggregates and the absence of parental consanguinity, however, fail to support the hypothesis of recessive inheritance. On the other hand, Milner et al11 reported X-chromatin-negative siblings with true hermaphroditism; additional cytogenetic studies were unavailable.
Two 46,XY true hermaphrodites12,13 developed gonadoblastomas, suggesting that 46,XY true hermaphrodites show the same predilection for neoplastic transformation as do individuals with 45,X/46,XY mosaicism or XY gonadal dysgenesis. Breast carcinoma has also been reported in 2 true hermaphrodites; one was 46,XX14 and the karyotype of the other15 is unknown.
The karyotype most often detected among true hermaphrodites is 46,XX. About 150 cases have been reported, including 40 among the Bantu and other African blacks.
A female sex of rearing was chosen in about one third of all 46,XY cases in which a sex assignment was made--much more often than in the 46,XY or 46,XX/46,XY groups. In fact, 1 true hermaphrodite16 was delivered of a male infant. Somatic anomalies were occasionally but not often present.
The gonadal distribution most commonly observed was a left ovary and a right ovotestis. The next most common was bilateral ovotestes (Table 1). Alternating gonadal distribution occurred less frequently in 46,XX true hermaphrodites than in 46,XY true hermaphrodites. One 46,XY true hermaphrodite developed a dysgerminoma14, and a second developed a gonadoblastoma17.
A uterus was present in 80% of the cases. Although still relatively high, this frequency is lower than that among 46,XY or 46,XX/46,XY true hermaphrodites. The uterus was sometimes unicornuate or bicornuate. As in true hermaphrodites with other karyotypes, a vas deferens and an epididymis were usually present ipsilateral to a testis, and a fallopian tube was usually present ipsilateral to an ovotestis. Occasionally, however, only wolffian derivatives or both müllerian and wolffian derivatives were present. Van Niekerk14,18 observed that 1) the fimbriated end of the fallopian tube was often occluded and 2) the cervical canal was often obliterated or characterized by squamous metaplasia. These observations have apparently not often been made by others19, leading one to wonder whether Van Niekerk's sample (all Bantu) indicates genetic heterogeneity among 46,XX true hermaphrodites.
In summary, 46,XX true hermaphrodites are more likely than other true hermaphrodites to have either a left ovary and a right ovotestis, or bilateral ovotestes. In particular, alternating hermaphroditism is less common than in 46,XY true hermaphrodites, and a uterus is less likely to be present.
In contrast to the apparent lack of heritability in other forms of true hermaphroditism, several familial aggregates of 46,XX true hermaphroditism have been reported. In 4 families20,21,22,23,24,25, multiple siblings had 46,XX true hermaphroditism. In contrast to 46,XX/46,XY or 46,XY true hermaphrodites, a uterus was present in only 2 of 10 patients, both in the same family. A male sex of rearing was chosen in 9 of 10 cases; puberal development was similar to that in other true hermaphrodites. These families indicate that at least one form of 46,XX true hermaphroditism results from an autosomal recessive gene or a factor that acts in similar fashion.
The presence of testicular tissue in individuals who apparently lack a Y chromosome could be explained by 1) undetected mosaicism or chimerism, 2) translocation of the Y testicular determinants to the X chromosome, 3) translocation of Y testicular determinants to an autosome, or 4) a mutant allele, or alleles. Let us consider each hypothesis.
First, in some cases undetected 46,XY cells are doubtless present. Cultures of testicular fibroblasts, however, sometimes show no 46,XY cells, although the complement in germ cells is unknown. In addition, cases with alternating hermaphroditism are those that theoretically appear most likely to have chimerism or mosaicism. Thus, the relatively low frequency of alternating gonads in 46,XX true hermaphrodites suggests that it would be unwise to assume in all cases the presence of undetected mosaicism.
Second, the presence of testicular tissue in 46,XX true hermaphrodites could result from translocation of Y-linked testicular determinants to an X chromosome or to an autosome (X-Y or X-autosome translocation). Supporting this hypothesis are 1) anomalous familial distributions of Xg alleles and 2) presence of H-Y antigen in most cases26,27. Presence of H-Y indicates Y-autosome or Y-X translocation of the Y-testicular determinant. Translocation of testicular determinants does not necessarily explain the true hermaphroditism phenotype; consideration of the following shows that other phenomena must simultaneously be postulated. If 1) H-Y antigen is the gene product of the testicular determinant and 2) the H-Y locus is translocated to an X chromosome or to an autosome, why is testicular differentiation abnormal in individuals who carry the translocation? That is, why are H-Y antigen-positive 46,XX true hermaphrodites not normal males? Wachtel27 notes that H-Y titer in these patients is lower than in 46,XY males. Thus, quantitative decrease in H-Y could be responsible.
Finally, the occurrence of familial aggregates suggests that some sporadic cases of 46,XX true hermaphroditism result from a mutant gene. Indeed, both dominant and recessive sex-reversal genes exist in animals1,2; lending credence to hypotheses that such genes may exist in humans. Such sex-reversed animals have been positive for H-Y antigens27. On the other hand, an X-Y or Y-autosome translocation in a paternal gonad could also explain sibship aggregates. Indeed, in one family13, both affected siblings were positive for H-Y antigen, suggesting either 1) X-Y or Y-autosome translocation in a line present in the father's testes or 2) activation of H-Y antigen through a mutation. The postulated mutant could thus interfere with H-Y antigen, or it could repress a male-determining locus controlled in regulatory fashion by the Y-testicular determinant(s). Unfortunately, few authors publish adequate genealogic data, and no H-Y data are available. It seems unlikely that all sporadic 46,XX true hermaphrodites could be explained on the basis of a mutant autosomal recessive allele, but some sporadic cases, especially those with bilateral ovotestes and no uterus, might result from such factors.
In addition to a recessive gene, an autosomal dominant sex-reversal gene might exist. Kasdan et al29 reported a kindred in which the proband was a 46,XX true hermaphrodite; both a “male” sibling and a paternal “uncle” showed complete sex reversal (46,XX males). In this family there thus appeared to be segregating a dominant factor capable of causing complete sex reversal (46,XX male), or if perhaps less completely expressed, 46,XX true hermaphroditism. A 46,XX male proband and probably a 46,XX true hermaphrodite sibling were also present in the family reported by Berger et al30; the true hermaphrodite sibling, said to be 46,XX/ 46,XY, had only two 46,XY cells studied prior to availability of banding techniques. Thus, it is uncertain whether the complement was 46,XX or 46,XX/46,XY. In addition, Chapelle et al reported a kindred in which 2 paternal second cousins were 46,XX males31,32.
Approximately 240 true hermaphrodites have been subjected to chromosome studies. The most common complement is 46,XX followed by 46,XX/ 46,XY; 46,XX/47,XXY; 45,X/46,XY; and others. In aggregate, true hermaphrodites are usually reared as males and usually develop breasts at puberty. Their external genitalia are most likely to resemble those of an incompletely virilized male. A true hermaphrodite may have a separate ovary and a separate testis, or one or more ovotestes. A uterus is usually present. The presence or absence of fallopian tubes or vasa deferentia reflects ipsilateral gonadal composition.
The diagnosis is usually not made prior to laparotomy. The following features, however, suggest the diagnosis of true hermaphroditism in a child with genital ambiguity: l) a gonad characterized by two consistencies (ovotestis), 2) a unicornuate or bicornuate uterus, 3) occlusion of fallopian tube fimbria, and 4) atresia or squamous metaplasia of the uterine cervix.
Neoplastic transformation of gonads can occur in true hermaphrodites. Specifically, gonadoblastomas or dysgerminomas have been reported in 2 46,XY, 2 46,XX/46,XY, and 2 46,XX true hermaphrodites. Two true hermaphrodites developed carcinoma of the breast; the karyotype of one was 46,XX, and the karyotype of the other was not determined.
Chimerism is the probable origin of 46,XX/46,XY true hermaphrodites. Almost all 46,XX/46,XY cases have a uterus, but no particular pattern of gonadal distribution predominated. True hermaphroditism of the types 46,XX/47,XXY and 45,X/46,XY probably results from nondisjunction. Neither type shows a distinct phenotype.
True hermaphrodites of the type 46,XY, the most common form of true hermaphroditism in Japan, are usually reared as males and usually have a uterus. Of 28 informative cases, 16 had alternating gonadal hermaphroditism; none or possibly 1 had bilateral ovotestes. In view of the frequent lack of thorough chromosome studies, these clinical features suggest that some 46,XY true hermaphrodites result from chimerism or mosaicism in which 46,XX cells are not readily detectable.
Nonfamilial 46,XX true hermaphrodites are probably of heterogeneous etiology. Some probably have mosaicism or chimerism in which 46,XY cells are not readily detectable, although analysis of testicular fibroblasts may fail to detect 46,XY cells. In other cases, Y-X or Y-autosome translocation is indicated by presence of the H-Y antigen in 46,XX true hermaphrodites.
The occurrence of at least 4 (sibling) aggregates of 46,XX true hermaphroditism indicates that an autosomal recessive allele, or a factor acting similarly, is responsible for at least one form of 46,XX true hermaphroditism. The familial cases are more likely to have bilateral ovotestes and more likely to lack a uterus than the nonfamilial cases. Some sporadic cases, particularly those with bilateral ovotestes and no uterus, might result from a mutant recessive allele. An autosomal dominant sex-reversal gene may also exist in humans. The mechanism of action appears to involve H-Y antigen, for both familial and nonfamilial cases are H-Y positive.
True hermaphroditism remains an etiologic enigma. In the past decade, strides have been made in elucidating the genetics of sex differentiation. The testis determining factor (TDF) has been localized to the short arm of the Y chromosome, probably in a 140 kb region.33 This DNA has properties of a zinc finger protein, and is believed to be involved in DNA transcription. Homologies with region on the X chromosome are consistent with suggestions by myself34 and others33,35,36 that the TDF may act in regulatory rather than in structural fashion. If this is the case, structural determinants for testicular differentiation may lie on the autosomes. This is relevant to the etiology of true hermaphroditism.
Another sex reversal disorder is 46,XX (sex-reversed) men--presence of testes in sterile but otherwise ostensibly normal 46,XX individuals. This disorder :results from interchange of TDF during paternal meiosis from the paternal Y to X.37 This etiology has been verified in over 80% of XX males.38 That TDF is not present in 46,XX true hermaphrodites39 suggests that the etiologies are fundamentally different in the two sex-reversal states.
If Y-X interchange is not the explanation for testes in individuals lacking a Y chromosome, autosomal factors must be considered. This gives added significance to cases of familial aggregates, referenced earlier. One additional family has been reported.40 Interestingly, at least some familial XX males lack TDF, thus not having undergone X-Y interchange.41 However, no evidence for increased parental consanguinity or unusual findings suggesting genetic heterogeneity were uncovered in the Bantu XX true hermaphrodites studied by Ramsay and co-workers.39
Conclusions concerning phenotypic changes alluded to in the discussion remain extant. Pregnancies in 46 XX true hermaphrodites are increasingly reported,42,43 including one in which pregnancy occurred without surgical corrections.42
23. Armendares S, Salamanca F, Cantu JM, del Castillo V, Nava S, Dominquez de la Piedra E, Cortes-Gallegos V, Gallegos A, Cervantes C, Parra A: Familial true hermaphroditism in three siblings: Clinical, cytogenetic, histological, and hormonal studies. Humangenetik 29: 99, 1975
24. Gallegos AJ, Guizar E, Armendares S, Cortes-Gallegos V, Cervantes C, Bedolla N, Parra S: Familial true hermaphroditism in three siblings: Plasma hormonal profiles and in vitro steroid biosynthesis in gonadal structures. J Clin Endocrinol Metab 42: 653, 1976
26. Wachtel SS, Koo GC, Breg WR, Thaler HT, Dillard DM, Rosenthal IM, Dosik H, Gerald PS, Saenger P, New M, Libere E, Miller OJ: Serologic detection of a Y-linked gene in XX males and XX true hermaphrodites. N Engl J Med 295: 750, 1976
34. Simpson JL: Phenotypic-karyotypic correlations of gonadal determinants: Current status and relationship to molecular studies. In Sperling K, Vogel F (eds): Human Genetics. Proceedings of 7th International Congress, Berlin, 1986. p 224. Heidelberg, Springer-Verlag, 1987