Arch. Biol. Med. Exp. 22: 1-13 (1989) Printed in Chile Disorders of gonadal development in humans

Desordenes del desarrollo gonadal en humanos

JOE LEIGH SIMPSON

Department of Obstetrics and Gynecology, Health Science Center, University of Tennessee, Memphis, TN38103, USA.

In humans, genes controlling sex differen­ gonads. Such cases permit the deduction tiation must be determined by deductive that testicular determinants are located reasoning. In the future the molecular basis on the Y short arm (Simpson, 1976). of genetic sex determinants should become Coupled with knowledge that males with evident, permitting new experimental ap­ ring or small metacentric Y chromosomes proaches. However, at present such investi­ have testes (German, Simpson, McLeMore, gation is still not possible. In humans we 1973), the Y-testicular determinant(s) can must survey the disorders of sex differen­ be localized near the centromere on Yp tiation in order to elicit clues into the con­ (Fig. 1). trol of normal sex reproduction. In this communication we shall summa­ rize current knowledge concerning genetic control of human sex differentiation. We shall focus upon selected disorders that Product(s) ofY allow localization of gonadal determinants Testicular Determinant to specific regions on the , ?H-Y Antigen on the Y chromosome, and on . We shall emphasize disorders of complete or nearly complete gonadal failure. Dis­ Testosterone Miillerian-Inhibitor Factor Wolffian Stabilization Miillerian Inhibition cussed elsewhere are several related condi­ Persistence of Seminal Regression of Uterus, Vesicles Fallopian Tubes, and tions, namely , male Vasa Deferentia Upper Vagina Epididymides pseudohermaphroditism, and female pseu­ 5a-Reductase A dohermaphroditism (Simpson, 1976, 1982, O Dihydrotestosterone 1985a). Genital Virilization 1^ Pftnis Scrotum Labioscrotal Fusion Fig. 1: Human testicular determinants are located near the centromere in the non-fluorescent region. From Simp­ son (1976). Y CHROMOSOME AND TESTICULAR DIFFERENTIATION We shall repeatedly observe in this The Y chromosome has long been known communication that an intact Y does not to direct testicular differentiation. In the assure normal testicular differentiation. past 10-15 years, analysis of individuals A variety of other loci must remain intact. with structural abnormalities of the Y has At this point one particular set of observa­ localized the Y-testicular determinant(s) to tions should be noted. In mice, Washburn a specific region. and Eicher (1983) have shown that a Y chromosome capable of directing testes A. Localization of Y-Testicular differentiation in some strains will fail Determinants to do so when the Y is transferred to cer­ tain other mouse strains. The latter strains Several 46,X,i(Yq) individuals have been possess a dominant mutant gene on chro­ reported (See Davis, 1981). All are female mosome No. 17. In those strains with the in appearance and all have bilateral streak mutant No. 17, only the Y specific for that 2 SIMPSON strain can direct normal testicular differen­ C. H-Y is Not the Gene Product of the tiation. We can conclude that autosomal Y-Testicular Determinant loci are integral for testicular development, that the effect of the Y-testicular determi­ Even if H-Y is integral for testicular differen­ nants is subject to regulation, and that the tiation, the phenomenon cannot be as­ Y-testicular determinants do not necessar­ cribed solely to H-Y antigen. Not only shall ily act identically within a given species. we see that most females with XY (Section IV) are H-Y positive (Wolf, 1979, Wolf et al, 1980a), but 45,X B. Evidence for H-Y Antigen Being Integral and 46,X,i(Xq) individuals are H-Y positive for Testicular Differentiation (Wolf et al, 1980b; Wolf, 1981) as well. Conversely, presence of ovaries in an XY The manner by which the testicular deter­ phenotypic female who had an additional minantes) acts is not totally understood, band on Yp has been observed (Bernstein but the consensus is that a cell surface et al, 1980). A potential explanation is antigen, H-Y antigen, is integrally involved that the additional band suppressed ex­ in testicular differentiation (Wachtel, 1983). pression of H-Y. Both circumstantial as well as direct evi­ dence suggests that H-Y antigen can direct It is thus clear that the Y-testicular testicular differentiation. The following determinant cannot correspond to the circumstantial data, referenced elsewhere structural locus for H-Y, for 45,X in­ by Wachtel (1983), are consistent with this dividuals obviously lack a Y. To be sure, hypothesis: 1) H-Y is evolutionarily conser­ H-Y titers in 45,X or 46,X,i(Xq) may be vative, in all species being present in that reduced. However, this merely suggests sex containing the heterogametic sex chro­ a threshold below which H-Y cannot direct mosome (Y or W); 2) one locus essential the indifferent gonad into a testis. If for H-Y expression is near or identical to H-Y indeed directs testicular differentiation, the locus for the testicular determinant(s); it follows that the Y-testicular determinant 3) H-Y is present in XY humans and mice must act in regulatory fashion. with insensitivity, indicating that If not located on the Y, the H-Y structu­ H-Y is not merely induced by , ral locus must be either autosomal or 4) H-Y continues to be expressed after H-Y X-linked. Its precise location remains cells are transferred to a female (XX) host; uncertain, but several observations are 5) H-Y is present in approximately 50% of noteworthy. First, the X contains at least mouse blastocysts, a stage prior to organ one locus that when mutant (i.e., XY differentiation and, hence, prior to gonadal dysgenesis) precludes testicular testicular differentiation, 6) sex-reversed differentiation. It would be logical to (46,XX) males and true hermaphrodites wonder whether this mutant involves the have H-Y antigen; and 7) H-Y antigen is locus whose wild type ordinarily directs present in the testicular but not the ovarian male development. However, most cases portion of ovotestes. In summary, H-Y is in of XY gonadal dysgenesis are H-Y positive, general considered present in individuals indicating that the mechanism of gene with testes, but not in those lacking testes. action need not involve an abnormality Direct evidence also exists. Reaggregation of H-Y synthesis. (H-Y receptors could of neonatal rodent testes disassociated by be absent or abnormal). Irrespective, if Moscona-type disruption produces tubular- H-Y is the key agent in testicular dif­ like (male) structures (Ohno et al, 1978, ferentiation, the XY gonadal dysgenesis Zenzes et al., 1978a). However, H-Y antisera locus and the H-Y structural locus cannot causes testicular cells to reaggregate into be one and the same. follicle-like (female) fashion. Moreover, One unifying scheme assumes an auto­ H-Y antigen recovered from cultured Sertoli somal location for the H-Y structural cells directs disassociated ovarian tissue locus. Perhaps the Y contains a regulatory into tubular-like structures (Zenzes et al, locus capable of suppressing second locus 1978b). on Xp. The Xp locus would otherwise DISORDERS OF GONADAL DEVELOPMENT 3 suppress the structural autosomal locus quences of such an exchange (Sections VI for H-Y. Alternatively, the H-Y structural and VII). locus could be on the X. Interestingly, At any rate, identification of Y-specific we have shown that there may exist not clones led to the logical hyphothesis that only an X-linked, H-Y antigen positive one of these DNA sequences might well form of XY gonadal dysgenesis but po­ direct testicular differentiation. Unfortu­ tentially also an autosomal recessive nately, Y-specific and many other probes form (i.e., genetic heterogeneity) (Simpson usually signify only repetitive DNA; unique et al., 1981). If the latter were H-Y antigen sequence DNA would more logically be negative, the mutant might correspond pivotal. Nonetheless, intriguing informa­ to the structural locus for H-Y. tion exists. Experience with one particular clone illustrates well the dilemma. A DNA sequence termed Bkm (banded D. Evidence that H-Y is Not Integral for krait minor satellite DNA) is highly con­ Testicular Differentiation served. It is present in heterogametic (female) snakes and heterogametic (male) McLaren and co-workers (1984) and Kiel- mice. The same sequence is present in sex- Metzger et al. (1985) do not believe that reversed XX (Sxr) mice. For these reasons, H-Y is pivotal to male differentiation. The one would expect Bkm to be a good former group not only found H-Y expres­ candidate for the testicular determinant. sion in some phenotypic female mice 8 1 However, Bkm hybridizes not to human carrying the Sxr (Sex-reversal) (X/X * ) Y chromosome DNA, but rather to the X mutant (E. Simpson et al, 1984), but 8 1 and to No. 6. (In the mouse, Bkm hy­ male (testes) differentiation in X/X * bridizes both to the Y and to No. 17, mice lacking H-Y (McLaren et al., 1984). as reported by Kiel-Metzger and Erickson, For this reason, various investigators have 1984). The ostensible conclusion is that turned to the possibility that certain Y- the Bkm sequences are not on the Y, and specific DNA sequences are pivotal. Of thus no longer a candidate for the primary course, DNA sequences would be expected Y-testicular determinant. On the other to control the Y-testicular determinant hand, it is possible that Bkm in humans necessary for H-Y expression. However, has too few copies (single copy) to permit the implication of "Y-specific sequences" hybridization, whereas in mice multiple in the present context is that such sequences copies readily display hybridization. Al­ bear no direct or indirect relationship to ternatively, Bkm sequences could still H-Y. be pivotal to testicular determination even Using conventional molecular methods, though located on an . Recall a host of DNA clones derived from the those studies showing that a locus on human Y have been isolated. Of 26 such murine No. 17 alters expression of the Y clones isolated by Bishop et al. (1984b), (Washburn and Eicher, 1983). Interestingly, 9 contained no homologous sequences the mouse 17 is probably homologous to elsewhere. The other clones showed ho­ the human 6, both chromosomes contain­ mology to autosomes or to the X chro­ ing the MHC locus. mosome. In fact, X-Y homology is now well accepted (Page et al., 1983, 1984), and considered the basis for X-Y pairing E. Conclusion Concerning Control of during meiosis (Bishop et al, 1984b). Testicular Differentiation Moreover, in 1973 the author and col­ The Y chromosome obviously remains leagues (German et al, 1973) proposed pivotal to male differentiation, but little that statural determinants existed on Xp else is absolutely certain. I personally and Yp, their pairing the basis of X-Y still favor an integral role for H-Y, but association. Exchange of X and Y segments contradictory data of McLaren et al. may lead to perturbations of sex de­ (1984) deserve attention. That the Y terminants, XX males and XX true her­ contains a regulatory but not a structural maphrodites representing clinical conse­ locus seems probable, but not assured. A 4 SIMPSON

Y-regulatory role must exist if H-Y or II X CHROMOSOME AND OVARIAN Bkm is essential, but not necessarily if DEVELOPMENT another mechanism or DNA sequence is essential. In the absence of a Y chromosome, or Irrespective, after having differentiated more specifically in the absence of H-Y from the indifferent gonad, the developing antigen, the indifferent gonad develops testes secrete two hormones (Fig. 2). into an ovary. This occurs in either 46,XX First, fetal Leydig cells produce an an­ or 45 ,X embryos. If two intact X chro­ drogen, probably testosterone. This mosomes are not present, most ovarian hormone stabilizes the Wolffian ducts to follicles degenerate by the time of birth. permit differentiation of vasa deferentia, We shall now review the various com­ epididymides and seminal vesicles. After plements associated with ovarian failure. conversion by 5 a-reductase to dihydro- Comparing phenotypes associated with testosterone, the external genitalia are specific X abnormalities will not only virilized. These actions can be mimicked show the basis for the above statements, by the administration of testosterone to but allow us to determine locations of female or castrated male embryos. This determinants necessary for oocyte main­ is demonstrated clinically by existence of tenance. By way of definition, this author teratogenic forms of female pseudoher­ applies the term "gonadal dysgenesis" to maphroditism. Second, fetal Sertoli cells any individual with streak gonads. The produce a second hormone, a non-steroid term "Turner stigmata" is reserved for hormone of high molecular weight that individuals with short stature and certain diffuses locally to cause regression of other somatic anomalies (Simpson, 1976). Mullerian derivatives (uterus and Fallopian The complement most frequently as­ tubes). The action of this hormone cannot sociated with gonadal dysgenesis is 45,X. be duplicated by any known compound. Approximately 50% of all patients with In the absence of the hormones described gonadal dysgenesis have a 45 ,X comple­ above, the external genitalia develop ment; 25% have sex chromosomal mosaicism along female lines; the Mullerian ducts without a structural abnormality (e. g., develop into a uterus and Fallopian tubes; 45,X/46,XX); the remainder have a and the Wolffian ducts regress. Again, these structurally abnormal X or Y or, more changes occur in 46,XX embryos and in often, no detectable chromosomal ab­ castrated 46,XY embryos. normality.

A. 45,X Statural Determinant(s) 1. Embryonic Lethality and its Cellular Explanation Ovarian Determinant (s) Approximately 50% of spontaneous abor­ tions occurring during the first three months of gestation are associated with a chro­ mosomal abnormality; 20% of chromo- somally abnormal abortuses are 45,X Ovarian Determinant (s) (Boué et al, 1978). Of all pregnancies, Statural Determinant(s) 12-15% terminate in first trimester spon­ taneous abortions; thus, 1-2% of all con­ ceptions must be 45,X. Because the in­ cidence of 45 ,X at birth is only about one per 10,000 females, over 99% of all 45,X Fig. 2: Probable location of the X chromosome of de­ embryos must be aborted. Intrauterine terminants necessary for ovarian-maintenance and for growth retardation is characteristic of sature. From Simpson and LeBeau (1981). the rare surviving 45,X neonate. DISORDERS OF GONADAL DEVELOPMENT 5

The high embryonic lethality, intra­ quantity. Although well differentiated, uterine growth retardation, and postnatal external genitalia, vagina, and Mullerian short stature could all be explained by a derivatives (uterus) remain small. 45 ,X prolonged 45 ,X cell cycle. Our group individuals are usually short (mean height believes that cell cycle time (CGT) is 141 cm) and show certain somatic prolonged in 45,X. In 1981 we showed anomalies. The most common anomalies that CGT was 22-24 hrs in adult 45 ,X are epicanthal folds, high-arched palate, fibroblasts, compared to 18-19 hrs in adult low nuchal hair line, webbed neck, shield 46,XX fibroblasts (Simpson & LeBeau, chest, coarctation of aorta, ventricular 1981). septal defect, renal anomalies, pigmented More recently, we have shown that nevi, lymphedema, nail hypoplasia, and cu­ 45 ,X cells are at a comparative disadvantage bitus valgus. No feature is pathognomonic, compared to 46,XX cells (Verp et al, but in aggregate they form a spectrum 1985). In artificial 45,X/46,XX mixtures, of anomalies more likely to occur in 45,X the frequency of the normal diploid line individuals than in other individuals. increases at the expense of the monosomic Because X chromosomes in excess of line. Prolonged CGT in 45,X could offer one are inactivated (Lyon hypothesis), an attractive pathogenic explanation for it is actually less obvious than one might several related phenomena-embryonic suspect that 45 ,X individuals should lethality, low birth weight, short stature. manifest developmental abnormalities. Even somatic anomalies could be explained Indeed, relatively normal ovarian develop­ because decreased cell number is ultimately ment occurs in 39,X mice, as well as in the mechanism of teratogenesis. most other X mammals. There are data supporting several related ex­ 2. Gonadal Development and Somatic planations for these findings: 1) Most Anomalies plausible is the hypothesis that some loci on the human heterochromatic (inactive) In the small percentage of 45 ,X individuals X are not truly inactivated, apparently who survive until adulthood, the normal unlike the situation in mice. For example, gonad is usually replaced by a white the locus for steroid sulfatase, which is fibrous streak, 2-3 cm long and about located on Xp21 -> pter, is, not inactivat­ 0.5 cm wide. The streak is located in the ed (Mohandes et al, 1979). It would not position ordinarily occupied by the ovary. be surprising if ovarian determinants like­ This streak gonad is characterized his­ wise escaped X-inactivation. 2) Moreover, tologically by interlacing waves of dense X-inactivation never occurs in human fibrous stroma, devoid of oocytes but oocytes (Gartler et al, 1972). Females otherwise indistinguishable from normal heterozygous for G6PD synthesize both ovarian stroma. Absence of oocytes in alleles in oocytes. 3) Theoretically, X- monosomy X is the result of increased inactivation might occur only after some oocyte atresia, not failure of germ cell crucial time of indifferentiation, beyond formation. Indeed, 45,X embryos and which only a single euchromatic (active) 45,X neonates have germ cell (Jirasek, X is necessary for continued oogenesis. 1976). Inasmuch as germ cells are present 4) Finally, all or part of the heterochromatic in 45,X embryos, it is not too surprising X could become reactivated. that occasional (3-5%) 45 ,X individuals Finally, the parental origin of 45,X menstruate spontaneously. Indeed, fertile is of genetic interest. Monosomy X (45,X) 45 ,X individuals have been reported (See may originate during oogenesis, during Simpson, 1981). spermatogenesis, or after fertilization. In Secondary sexual development does not, humans 70% of liveborn 45,X individuals however, usually occur in 45 ,X individuals. have lost a paternal sex chromosome and androgen levels are decreas­ (Sanger et al, 1977). In neither 45,X ed; FSH and LH are increased. Pubic and abortuses nor liveborns is the mean ma­ axillary hair fail to develop in normal ternal age increased (Kajii & Ohama, 6 SIMPSON

BREAST DEVELOPMENT SPONTANEOUS MENSTRUATION 1979), an observation consistent with KXp)=dd(Xq) >(Xp>*

B. 45,X/46,XX and Related Mosaicisms 5/18 45,X/46,XX individuals have fewer anomalies than 45,X individuals. In one survey by the author, 12% of 45,X/46,XX individuals menstruated, compared to only 3% of 45,X individuals (Simpson, 1975). The mean adult height is greater in 45 ,X/ 46,XX (146 cm) than in 45,X individuals Fig. 3: Frequencies of spontaneous menstruation and (142 cm). More (25%) than non- breast development in X-deletions. Two tabulations are mosaic (5%) patients reach adult heights prepared, depending upon whether 46,X,i(Xp) truly greater than 152 cm. Somatic anomalies exists or whether reported cases are actually 46,X,del(X) are less likely to occur in 45,X/46,XX (q24). Modified from Simpson and LeBeau (1981). than in 45,X patients. More recently, we are questioning del(X) (pi 1) and 146 cm in 46,X,del(X) whether even the 12% menstruation fre­ (p21 or 22) (Simpson & LeBeau, 1981). quency is not underestimated. All 45,X/ Inasmuch as 46,X,del(x) (p21) individuals 46,XX cases ascertained in our unit, which are short yet show normal ovarian function, is based in a maternity hospital, have ovarian determinants and statural de­ menstruated (Simpson et al, 1986). We terminants must be located in different suspect that biases of ascertainment are regions of Xp; statural determinants are influencing the perception of the pheno- more distal (Fig. 4). My conclusions are type, with prognosis for 45,X/46,XX better similar in this respect to those of others than initially suspected. (Goldman et al, 1982). Analogous to the situation with respect C. of the X Short Arm to Y-specific DNA probes, there is as yet [del (Xp)] no evidence that any given X-specific probe bears special relationship to X- A deletion of the X short arm may or may ovarian or X-structural determinants. not cause gonadal dysgenesis, short stature and other features of the Turner stigmata. D. Isochromosome for the X Long Arm The phenotype depends upon the amount [i(Xq)] of Xp that is deficient. Spontaneous menstruation, albeit usually Almost all 46,X,i(Xq) patients have streak leading to secondary amenorrhea, has gonads, short stature, and features of the occurred in almost 40% of reported 46,X, Turner stigmata. In addition to having a del(X) (pi 1) individual (Fig. 3). Almost all duplication of Xq, i(Xq) subjects differ 46,X,(del(X) (p21) individuals menstruate from del(X) (p 11) subjects because not (Fraccaro et al, 1977). Elsewhere I provide only the terminal portion but almost complete references (Simpson, 1985a). all of Xp is deleted. This difference could These data not only indicate that ovarian indicate that gonadal determinants are tissue persists more often in del(Xp) present at several different locations on individuals than in 45 ,X individuals, but Xp. A locus on Xp might be deleted in also that ovarian failure occurs only if (Xq), yet retained near the centromere both the proximal and terminal portions in 46,X,del(X) (pi 1). Duplication of of Xp are deleted. On the other hand, Xq (i.e. 46,X,i(Xq)) does not compensate the mean adult height is 140 cm in 46 ,X, for deficiency of Xp; thus, gonadal deter- DISORDERS OF GONADAL DEVELOPMENT 7 minants on Xq and Xp must have different F. OtherXAbnormalities functions. Whether duplication of Xqper se produces abnormalities is unknown. Centric fragments and ring [r(X)] chromo­ somes are often mitotically unstable; thus, E. Deletion of the X Long Arm [del(Xq)] phenotypic-karyotypic correlations are hazardous because monosomic lines are Many patients with a deletion of the X long frequently associated. However, some in­ arm never menstruate, having streak gonads dividuals with ring (X) chromosomes (Fig. 3). That X autosomal translocations menstruate and show normal breast de­ involving the region Xql3 -»• 26 usually are velopment. This further confirms that not associated with sterility (Mattei et al., all gonadal determinants are telomeric, as 1981; Madan, 1983) indicates either that postulated with Figure 4. important ovarian determinants exist in this region or that the entire region must remain unperturbed ("critical") for ovarian in function. Since menstruation and breast AUTOSOMAL GENES AND OVARIAN development have on occasion been ob­ DEVELOPMENT served in individuals with del(Xq) or In addition to X-determinants, it can be X/autosome translocation involving Xq, I deduced that autosomal genes are also believe that the critical region hypothesis pivotal for ovarian development. needs revision. Perhaps several loci can affect ovarian function in additive fashion. A. Gonadal Dysgenesis in 46,XX If so, their precise location remains un­ Individuals certain because the presence or absence of gonadal function cannot be correlated readily with the amount of Xq that is Decourt et al. (1960) reported the first absent. individual with gonadal dysgenesis and an apparently normal female (46,XX) com­ It originally appeared that deletion of plement. By 1971 Simpson et al. (1971a) Xq did not result in short stature (Fergu­ accumulated 61 individuals with XX son-Smith et al., 1964; Simpson, 1975). gonadal dysgenesis and concluded that Our more recent tabulations show de­ the disorder was inherited in autosomal creased mean height (152 cm) in del(X) recessive fashion. (q22) and (q24) (Simpson & LeBeau, External genitalia and streak gonads in 1981). These data suggest the existence XX gonadal dysgenesis are indistinguishable of a statural determinant of Xq (Fig. 4). from those in gonadal dysgenesis due to a sex chromosomal abnormality. Likewise, the endocrine profiles do not differ. How­ ever, individuals with XX gonadal dysgenesis are usually normal in stature. Several pa­ Testicular Determinant(s) thogenic mechanisms can be postulated, but firm data have not been gathered. Phenocopies for XX gonadal dysgenesis are also well recognized-autoimmune dis­ ease, irradiation, hemorrhage, and mumps. Both XX gonadal dysgenesis and neuro­ sensory deafness have occurred in multiple sibs in several families (Pallister & Opitz, 1979); occurrence of deaf but fertile male sibs confirms autosomal inheritance. The coexistence of gonadal and auditory anomalies probably indicates a syndrome Fig. 4: Schematic diagram illustrating male sex differen­ distinct from XX gonadal dysgenesis with­ tiation. From Simpson (1980). out deafness (i.e., genetic heterogeneity). 8 SIMPSON

Indeed, further evidence for genetic hetero­ well accepted that at least one form of XY geneity can be cited. In at least four other gonadal dysgenesis results from an X-link­ families (see Simpson, 1985a), unique ed recessive or male-limited autosomal patterns of somatic anomalies indicate the dominant gene (Stenberg et al, 1968; existence of mutant genes distinct from Simpson et al, 1981). An autosomal reces­ those already discussed. sive form may exist as well (Simpson et al, 1981). B. Polycystic Ovarian Disease H-Y antigen studies in affected indiv­ iduals were awaited with great expectation, Polycystic ovarian disease is a relatively especially after it became known that an common disorder characterized by obesity, analogous disorder in Swedish wood lem­ oligomenorrhea, and hirsutism. Physicians mings (Myopus schistocolor) was the result appreciate the varied traits shown by of an X-linked mutant that apparently affected individuals, who often require suppressed H-Y antigen (Wachtel et al, ovulation inducing agents to achieve preg­ 1976). Unexpectedly, some humans with nancy. The disorder is characterized by XY gonadal dysgenesis showed H-Y anti­ increased LF/FSH ratio, elevated andro- gen, whereas others did not (Wolf, 1981). stenedione and increased peripheral con­ Neoplasia appears to occur more com­ version of androstenedione to estrone. monly in H-Y positive forms (Wolf, 1981; Heritable tendencies clearly exist, but Mann et al, 1983). In addition to showing their nature is uncertain. Autosomal genetic heterogeneity, these data raise the dominant or possibly X-linked dominant possibility that embryonic gonads in XY inheritance has been proposed (Cohen et gonadal dysgenesis may sometimes be al, 1975). A single gene may not exist, testes and sometimes ovaries. Histologic but heritable tendencies probably indicat­ support for this hypothesis also exists. In ing autosomal loci are clear (Simpson, particular, oocytes were detected in a 1985b). human neonate with XY gonadal dys­ genesis (Cussen & MacMahon, 1979). Per­ rv haps such cases will all prove H-Y negative AUTOSOMAL AND X-LINKED GENES NECESSARY and at low risk for neoplasia. FOR TESTICULAR DEVELOPMENT Further evidence for genetic hetero­ Analogous to genes integral to ovarian geneity lies in existence of the syndrome development, we can deduce that genes of H-Y-negative XY gonadal dysgenesis and other than those on the Y are integral to long-limbed campomelic dwarfism (Brica- testicular development. In Section I we relli et al, 1981). Again, gonads may even have already seen that normal testicular resemble ovaries (sex reversal) (Schimke, differentiation might well even be directed 1979). In addition, Brosnan et al (1980), by an X-linked or autosomal locus. In fact, reported a distinctive syndrome in which if H-Y is integral, it is essential that such a 46,XY "female" sibs displayed streak locus exists. A few illustrative disorders will gonads, unusual facies, cardiac anomalies, suffice to show the necessity for genes renal anomalies, ectodermal abnormalities beyond those on the Y. like scalp defects, and mental retardation. XY gonadal dysgenesis has been associated A. Gonadal Dysgenesis in 46,XY with yet other multiple malformation Individuals patterns, namely one characterized by facial asymmetry, prominent forehead, Gonadal dysgenesis can occur in 46,XY cleft palate, ventricular septal defect, and individuals. In XY gonadal dysgenesis, skeletal abnormalities. affected individuals are phenotypic females who show sexual infantilism and bilateral B. Agonadia streak gonads. The gonads may undergo neoplastic transformation (20-30% preva­ In agonadia 46,XY individuals show absent lence) (Simpson & Photopulos, 1976). It is or abnormal external genitalia and ru- DISORDERS OF GONADAL DEVELOPMENT 9

dimentary Mullerian or Wolffian derivatives. D. Syndrome of Rudimentary Testes External genitalia usually consist of 1) a phallus about the size of a clitoris, 2) nearly Bergada et al. (1962) reported four unre­ complete fusion of the labioscrotal folds, lated males who, despite well-formed testes and 3) often a persistent urogenital sinus. less than 1 cm in greatest diameter, had By definition, gonads cannot be detected small penises. Their testes consisted of (agonadia). Likewise, neither normal Mulle­ small tubules containing Sertoli cells, a few rian derivatives nor normal Wolffian de­ Leydig cells, and an occasional spermato­ rivatives are present; however, structures gonium. Wolffian derivatives were present; resembling a rudimentary Fallopian tube, Mullerian derivatives were absent. The an epioophoron, or an epididymis may pathogenesis is unclear. However, testes be detected along the lateral pelvic wall. were presumably normal during early em- Somatic anomalies are common-cranio­ bryogenesis, only later decreasing in size. facial anomalies, vertebral anomalies, and Najjar et al. (1974) reported five affected mental retardation. sibs. Any explanation for agonadia must explain not only the absence of gonads, E. Anorchia but also abnormal external genitalia and lack of normal internal ducts. At least Males with anorchia have unambiguous two explanations seem reasonable: 1) fetal male external genitalia, normal Wolffian testes functioned sufficiently long to in­ derivatives, no Mullerian derivatives, and no hibit Mullerian development, yet not detectable testes. Vasa deferentia terminate sufficiently long to complete male dif­ blindly. Unilateral anorchia is not extra­ ferentiation, or 2) the entire gonadal, ordinarily rare, but bilateral anorchia is. ductal and genital systems developed Even in bilateral anorchia the penis is well- abnormally, as result of either defective differentiated. Paghogenesis presumably anlage, defective connective tissue, or involves atrophy of fetal testes after oc­ action of a teratogen. The frequent co­ currence of genital virilization during existence of somatic anomalies supports weeks 8-11 of embryonic development. existence of either a teratogen or defective Heritable tendencies exist, although the connective tissue. Affected sibs have been occurrence of monozygotic twins discor­ reported; thus, a genetic etiology should dant for anorchia suggests that genetic be considered, possibly one affecting factors are not paramount in all cases connective tissue. H-Y antigen is present (Simpson etal, 1971b). (Schulte, 1979), suggesting that patho­ genesis does not involve an abnormality F. Mutant Genes Affecting of this system. Spermatogenesis and Spermiogenesis

In plants and lower animals many aspects C. Ley dig Cell Agenesis of meiosis are known to be under genetic control. Especially well documented is the A few 46,XY patients have been reported existence of genes affecting spermiogenesis to have complete absence of Leydig cells, in bulls. Similar genus surely exist in hu­ precluding embryonic virilization (Berthe- mans, and their mutation should deleter- zene et al, 1976). They showed normal iously affect reproduction. Indeed, in some female external genitalia or posterior labial families genes interfering with male meiosis fusion, no uterus and bilateral testes devoid lead to infertility (Chaganti et al, 1980). of Leydig cells. Lack of a uterus distin­ Carson et al. (1983) studied a male whose guishes these patients from XY gonadal spermatozoa showed a 4C DNA count; dysgenesis. Presence of testes excludes two sibs were similarly affected, indicating agonadia. Lack of breast development autosomal recessive inheritance. Additional excludes complete androgen insensitivity evidence for meiotic mutants causing hu­ (testicular feminization). man infertility will doubtless be uncovered. 10 SIMPSON

V. minal position of the testes. A uterus is KLINEFELTER SYNDROME usually present, albeit often bicornuate or unicornuate. Reviewed elsewhere by the author in detail About two thirds of true hermaphro­ (Simpson, 1976), these well-known disor­ dites are raised as males, although external ders are characterized by seminiferous genitalia may be ambiguous or predomin­ tubule dysgenesis. 47,XXY individuals antly female. Paradoxically, breast develop­ always show this trait, and its associated ment usually occurs at , despite sterility and hypoandrogenism. Somatic predominantly male external genitalia; anomalies may or may not be present. virilization usually does not. Most true However, 48,XXXY and 49,XXXXY in­ hermaphrodites with a uterus menstruate, dividuals inevitably show not only sterility and some 46,XX true hermaphrodites have but also mental retardation and other become pregnant (see Simpson, 1981). somatic anomalies. The etiology of true hermaphroditism These disorders make it clear that tes­ is heterogeneous. Most 46,XX/46,XY cases ticular development is adversely affected probably result from chimerism. However, in males with more than one X chromo­ experimental production of XX/XY mouse some. The actual pathogenesis is unclear. chimeras does not always result in true Probably seminiferous tubule dysgenesis hermaphroditism, nor do all 46,XX/46,XY is caused by either: 1) altered cellular humans have true hermaphroditism. The milieu secondary to added chromatin, or presence of testicular tissue in 46,XX true 2) loci that are not inactivated, therefore hermaphrodites is perplexing because tes­ causing imbalance. If the latter were res­ ticular development has occurred in the ponsible, monogenic factors would seem ostensible absence of the Y chromosome. unlikely to be involved. Indeed, the con­ Reasonable hypotheses include: 1) trans­ sistency with which seminiferous dys­ location of the Y-testicular determinant(s) genesis exists excludes usual genetic hypo­ to an X or to an autosome, 2) undetect­ theses. ed mosaicism or chimerism, and 3) sex- reversal genes. The first or possibly the second hypothesis seems most likely in VI view of H-Y antigen being present in almost TRUE HERMAPHRODITISM all 46,XX true hermaphrodites (Wachtel, 1983). Especially impressive is the presence True hermaphrodites possess both ovarian of H-Y antigen in each of two 46,XX true and testicular tissue. Most true herma­ hermaphrodite sibs (Fraccaro et al, 1979). phrodites are 46,XX; however, a minori­ ty are 46,XX/46,XY, 46,XX/47,XXYY, 46,XY, or other complements (Van Nie- kerk & Retief, 1981; Simpson & Sarto, VII 1978). 46,XX MALES (SEX-REVERSAL) Gonads may consist of one ovary and one testis, or more often, one or more 46,XX (sex-reversed) males are pheno- ovotestes. In 80% of ovotestes the testicular typic males with bilateral testes. Affected and ovarian components are juxtaposed individuals have small testes and show signs end-to-end. One unexplained observation of androgen deficiency similar to 47,XXY is that a testis or an ovotestis is more likely Klinefelter syndrome. The penis and to be present on the right than the left. In­ scrotum are small but usually well differ­ terestingly, in birds the right gonad is entiated; Wolffian derivatives are normal. known to develop preferentially into a Seminiferous tubules are decreased in testis. In human true hermaphrodites sper­ number and in size, Leydig cells are hyper­ matozoa are rarely present; however, plastic, and spermatogonia are not usually apparently normal oocytes are often present. present, even in ovotestes. Presumably As in 46,XX true hermaphrodites, testes this difference relates to the intraabdo­ in 46,XX males develop contrary to expect- DISORDERS OF GONADAL DEVELOPMENT 11 ations that a Y chromosome is required for responsible for sex determination in testicular differentiation. Again, 46,XX mammals (i.e., X-Y) and in dipteran males show H-Y antigen (Wachtel, 1983); species (i.e., X-autosomal balance) may thus, X-Y or Y-autosome translocation not be so disparate as usually assumed. seems the likely etiology. This is highly Finally, we have not even considered consistent with molecular studies indicat­ the many different genes that must remain ing: 1) homology between the X and Y intact for external and internal genital de­ (Bishop et al. 1984a), 2) hybridization of velopment. Chromosomal factors are not Y-specific probes in human XX males paramount, but both monogenic (mend- (Guellan et al, 1984), 3) paternal origin elian) as well as polygenic factors have been of one X shown by X-restriction fragment identified readily by ourselves and by length polymorphisms (Page & De la Cha- others. pelle, 1984).

Familial aggregates of either 46,XX REFERENCES males alone, or 46,XX males and 46,XX true hermaphrodites, have been reported. 1. BISHOP, C; GUELLAEN, G.; GELDWORTH, D.; FELLOWS, M.; WEISSENBACH, J. (1948a) Exten­ In one well-studied kindred, mothers of sive sequence homologies between Y and other human affected cousins were H-Y positive (Wachtel chromosome. J. Mol. Biol. 173: 403-417. et al, 1981). One possible explanation is 2. BISHOP, C.E.; GUELLAEN, G.; GELDWERTH, D.; VOSS, R.; FELLOWS, M.; WEISSENBACH, J. the existence of a Y-X or Y-autosome (1984b) Single-copy DNA sequences specific for the translocation involving portions of H-Y human Y chromosome.Nature 309: 253-255. genes that are ordinarily present in multiple 3. BERGADA, C; CLEVELAND, W.W.; JONES, H.W.; WILKINS, L. (1962) Variants of embryonic testicular copies. Unaffected females might transmit dysgenesis: Bilateral anorchia and the syndrome of a translocated portion of the Y, too small rudimentary testes. Acta Endocrinol. Copenhagen to confer maleness but sufficiently large 40: 521-536. to behave in recessive sex-reversal fashion 4. BERNSTEIN, R.; JENKINS, T.; DAWSON,B.; WAG­ NER, J.; DEWALD, G.; KOO, G.C.; WACHTEL, S.S. if a spouse were heterozygous for a similar (1980) Female phenotype and multiple abnormalities mutant (Wachtel et al, 1981). Familial in sibs with a Y chromosome and partial X chromo­ some duplications: H-Y antigen and Xg blood group aggregates and data consistent with this findings. /. Med. Genet. 1 7: 291-300. hypothesis have been made in XX true 5. BERTHEZENE, F.; FOREST, M.G.; GRIMAUD, hermaphrodite dogs (Selden et al, 1978). J.A.; CLANSTRAT, B.; MORNEX, R. (1976) Leydig In addition, sex-reversed goats (Polled), cell agenesis: A cause of male pseudohermaphrodi­ tism. N. Engl. J. Med. 295: 969-972. and mice (Sxr), disorders homologous 6. BOUE, J.; BOUE, A.; LAZAR, P. (1975) Retro­ to human sex-reversal, are generally accept­ spective and prospective epidemiological studies of ed as showing H-Y antigen (Wachtel, 1983). 1,500 karyotyped spontaneous humans abortions. Teratology 12: 11-26. However, we have already noted (Section I) 7. BRICARELLI, F.D.; FRACCARO, M.; LINDSTEN, the claim that male Sxr mice (X/XSxr) may J.; MULLER, U.; BAGGIO, P.; CARBONE, L.D.L.; be H-Y negative (McLaren et al, 1984). HJERPE, A.; LINDGREN, F.; MAYEROVA, A.; RINGERTZ, H.; RITZEN, E.M.; ROVETTA, D.C.; Assay vicissitudes could explain this dis­ SICCHERO, C; WOLF, U. (1981) Sex-reversed XY crepancy. females with campomelic dysplasia are H-Y negative. Hum. Genet. 57: 15-22. 8. BROSNAN, P.G.; LEWANDOWSKI, R.C.; TOGURI, A.G.; PAYER, A.F.; MEYER, W.J. (1980) A new VIII familial syndrome of 46,XY gonadal dysgenesis with CONCLUSION anomalies of ectodermal and mesodermal structural. /. Pediatr. 97: 586-590. The data we have considered makes it obvi­ 9. CARSON, S.A.; RAO, R. (1983) Mutant gene causing large sperm heads with multiple tails. Abstracts, 30th ous that genetic control of human sex Annual Meeting, Society for Gynecologic Investiga­ differentiation is complex, and only tion, p. 27. beginning to be elucidated. Genes or, 10. CHAGANTI, R.S.K.; JHANWAR, S.C.; EHREN- BARD, L.T.; KOURIDES, I.A.; WILLIAMS, J.J. more precisely, at least determinants, (1980) Genetically determined asynapsis, spermato- exist on the X, on the Y, and on auto­ genic degeneration and infertility in men. Am. J. somes. All must interact appropriately for Hum. Genet. 32: 833-848. 11. COHEN, P.N.; GIVENS, J.R.; WISER, W.L.; WIL- normal gonadal development. Such ob­ ROY, R.S.; SUMMITT, R.L.; COLEMAN, S.A.; servations imply that the mechanisms ANDERSON, R.N. (1975) Polycystic ovarian dis- SIMPSON

ease, maturation arrest of spermatogenesis and 28. MATTEI, M.; MATTEL J.F.; VIDAL, I.; GIRAUD, Klinefelter's syndrome in siblings of a family with F. (1981) Structural anomalies of the X chromo­ familial hirsutism. Fertil. Steril. 26: 1228-1238. some and inactivation center. Hum. Genet. 56: CUSSEN, L.J.; MACMAHON, R.A. (1979) Germ 401-408. cells and ova in dysgenetic gonads of a 46.XY female 29. MOHANDES, T.; SHAPIRO, L.J.; SPARKERS, dizygotic twin. Arch. J. Dis. Child. 133: 373-375. R.S.; SPARKES, M.C. (1979) Regional assignment DAVIS, R.M. (1981) Localization of male determin­ of the steroid sulfatase-X-linked ichthyosis locus: ing factors in men: A thorough review of structural Implications for a noninactivated region on the anomalies of the Y chromosome. /. Med. Genet. 18: short arm of human X-chromosome. Proc. Natl. 161-195. Acad. Sci. USA 76: 5 7 79-57 8 3. DECOURT, J.; MICHAUD, J.P.; DELZANT, G. 30. MCLAREN, A.; SIMPSON, E.; TOMONARI, K.; (1960) Syndrome de Turner avec caryotype feminin CHANDLER, P.; HOGG, H. (1984) Male sexual normal. Rev. Fr. Endocrinol. Clin. Nutr. Metab. 1: differentiation in mice lacking H-Y antigen. Nature 321-331. 312: 552-555. FERGUSON-SMITH, M.A.; ALEXANDER, D.S.; 31. NAJJAR, S.S.; TAKLA, R.J.; NASSAR, V.H. (1974) BO WEN, P.; GOODMAN, R.M.; KAUFMAN, B.N.; The syndrome of rudimentary testes: Occurrence JONES, H.W. Jr.; HELLER, R.H. (1964) Clinical in five siblings. Pediatrics 84: 119-122. and cytogenetical studies in female gonadal dys­ 32. PAGE, D.; WYMAN, A.; BOTSTEIN, D. (1983) genesis and their bearing on the cause of Turner's Homologous single-copy sequences on the human syndrome. Cytogenetics 2: 142-155. X and Y chromosomes. In Recombinant DNA FRACCARO, M.; MARASCHIO, P.; PASQUALI, Applications to Human Disease. Banbury Report F.; SCAPPATICCI, S. (1977) Women heterozygous N° 14, eds. C.T. Caskey, R.L. White. Cold Spring for deficiency of the (p21 -*• pter) region of the X Harbor Laboratory, pp. 267-273. chromosome are fertile. Hum. Genet. 39: 283-291. 33. PAGE, D.; DE LA CHAPELLE, A. (1984) The FRACCARO, M.; TIEPOLO, L.; ZUFFARDIO- parenteral origin of X chromosome in XX males CHIUMELLO, G.; DINATALE, B.; GARGANTINI, determined using restriction fragment length poly­ L.; WOLF, U. (1979) Familial XX true herma­ morphisms. Am. J. Hum. Genet. 35: 565-575. phroditism and the H-Y antigen. Hum. Genet. 48: 34. PALLISTER, P.D.; OPITZ, J.M. (1979) The Perrault 45-52. syndrome: Autosomal recessive ovarian dysgenesis GARTLER, S.M.; LISKAY, R.M.; CAMPBELL, with facultative, non-sex-limited sensorineural deaf­ B.K.; SPARKES, R.; GANT, N. (1972) Evidence of ness. Am. J. Med. Genet. 4: 239-246. two functional X chromosomes in human ococytes. 35. RUSSELL, L.B. (1962) Chromosome aberrations in Cell. Differ. 1: 215-218. experimental mammals. Prog. Med. Genet. 2: 230- GERMAN, J.; SIMPSON, J.L.; MCLEMORE, G.A. 294. (1973) Abnormalities of human sex chromosomes. 36. SANGER, R.; TIPPETT, P.; GAVIN, J.; TEESDA- I. A ring Y without mosaicism. Ann. Genet. 16: LE, P.; DANIELS, G.L. (1977) Xg groups and sex 225-231. chromosome abnormalities in people of northern GUELLAEN, C; CASANOVA, M.; BISHOP, C; European ancestry: An addendum. /. Med. Genet. GELWERTH, D.; ANDRE, G.; FELLOWS, M.; 14: 210-211. WEISSENBACH, J. (1984) Human XX males with 37. SARTO, G.E.; SIMPSON, J.L. (1978) Abnormalities Y single copy. DNA fragments. Nature 307: 172- of the Mullerian and Wolffian duct systems. Birth 173. Defects 14 (6c): 37-54. GOLDMAN, B.; POLANI, P.E.; DAKER, M.G.; 38. SCHJMKE, R.N. (1979) XY sex-reversal campomelia ANGELL, R.R.. (1982) Clinical and cytogenetic possibly and X-linked disorder? Clin. Genet. 16: aspects of X-chromosomal deletions. Clin. Genet. 62-63. 21: 36-52. 39. SCHULTE, M.J. (1979) Positive H-Y antigen testing JIRASEK, J. (1976) Principles of reproductive in a case of XY gonadal absence syndrome. Clin. embryology. In Disorders of Sexual Differentiation: Genet. 16: 438-440. Etiology and Clinical Delineation, ed. J.L. Simpson. 40. SELDEN, J.R.; WACHTEL, S.S.; KOO, G.C.; HAS- New York: Academic Press, pp. 51-110. KINS, M.E.; PATTERSON, D.F. (1978) Genetic KAJII, T.; OHAMA, K. (1979) Inverse maternal age basis of XX male syndrome and XX true herma­ effect in monosomy X. Hum. Genet. 51: 147-151. phroditism: Evidence in the dog. Science 201: KIEL-METZGER, K.; ERICKSON, R.P. (1984) 644-646. Regional localization of sex-specific Bkm-related 41. SIMPSON, E.; MCLAREN, A.; CHANDLER, P.; sequences on proximal of mice. TOMONARI, K. (1984) Expression of H-Y antigen Nature 310: 575-581. by female mice carrying Sxr. Transplantation 37: KIEL-METZGER, K.; WARREN, G.; WILSON, G.; 17-21. ERICKSON, R.P. (1985) Evidence that the human 42. SIMPSON, J.L. (1975) Gonadal dysgenesis and Y chromosome does not contain clustered DNA abnormalities of the human sex chromosomes: sequences (BKM) associated with heterogametic Current status of phenotypic-karyotypic correla­ sex determination in other vertebrates. N. Engl. tions. Birth Defects 11 (4): 113-159. J. Med. 313: 242-245. 43. SIMPSON, J.L. (1976) Disorders of Sexual Differen­ MAD AN, K. (1983) Balanced structural changes tiation: Etiology and Clinical Delineation. New involving the human X: Effect on sexual pheno- York: Academic Press. type. Hum. Genet. 63: 216-221. 44. SIMPSON, J.L. (1980) Genetics of human repro­ MANN, J.R.; CORKERY, J.J.; FISHER, H.J.W.; duction. In Human Reproduction, ed. E.S.E. Hafez. CAMERON, A.H.; MAYEROVA, A.; WOLF, U.; Hagerstown: Harper & Row, 2nd ed., pp. 395-411. KENNAUGH, A.A.; WOOLLEY, V. (1983) The 45. SIMPSON, J.L. (1981) Pregnancies in women with X linked recessive form of XY gonadal dysgenesis chromosomal abnormalities. In Genetic Diseases with high incidence of gonadal cell tumors: Clinical in Pregnancy, ed. J.D. Schulman, J.L. Simpson. New and genetic studies. /. Med. Genet. 20: 264-270. York: Acadmic Press, pp. 440-471. DISORDERS OF GONADAL DEVELOPMENT 13

46. SIMPSON, J.L. (1982) Genetic disorders of gonadal 56. VAN NIEKERK, W.A.; RETIEF, A!E. (1981) The development in humans. In Genetic Control of gonads of human true hermaphrodites. Hum. Genet. Gamete Production and Function, eds. P.G. Crosig- 58: 117-122. nani, B.L. Rubin. London: Academic Press, pp. 199- 57. VERP, M.S.; ROSINSKY, B.; LEBEAU, M.M.; MAR­ 228. TIN, A.O.; KAPLAN, R.; WALLERMARK, C.-B.; 47. SIMPSON, J.L. (1985a) Ovarian failure (Gonadal SIMPSON, J.L. (1985) Selective growth disadvantage dysgenesis). In Progress in Infertility, eds. J. Behr- of fibroblasts with 45 ,X or X-structural abnormalities. man, G. Patton, 3rd. ed., in press. Abstracts, Amer. J. Hum. Genet. 48. SIMPSON, J.L. (1985b) Genes causing female in­ 58. WACHTEL, S.S. (1983) H-Y Antigen and the Biolo­ fertility. Fertil Steril, in press. gy of Sex Determination. New York: Academic 49. SIMPSON, J.L.; LEBEAU, M.M. (1981) Gonadal Press. and statural determinants on the X chromosome 59. WACHTEL, S.S.; BASRUR, P.; KOO, G.C. (1981) and their relationship to in vitro studies showing Recessive male-determining genes. Cell. 15: 279- prolonged cell cycles in 45,X; 46,X,del(X) (pll); 281. 46,X,del(X) (ql3); and 46,X,del(X) (q22) fibro­ 60. WACHTEL, S.S.; KOO, C; OHNO, S.; GROPP, A.; blasts. Amer. J. Obstet. Gynecol. 141: 930-938. DEV, V.G.; TANTRAVAHI, R.; MILLER, D.A.; 50. SIMPSON, J.L.; PHOTOPULOS, G. (1976) The MILLER, O.J. (1976) H-Y antigen and the origin relationship of neoplasia to disorders of abnormal of XY female wood lemmings (Myopus schistocolor). sexual differentiation. Birth Defects 12 (1): 15-50. Nature 264: 638-639. 61. WASHBURN, L.L.; EICHER, E.M. (1983) Sex re­ 51. SIMPSON, J.L.; BLAGOWIDOW, N.; MARTIN, versal in XY mice caused by dominant mutation on A.O. (1981) XY gonadal dysgenesis: Genetic hetero­ chromosome 17. Nature 303: 338-340. geneity based upon clinical observations, H-Y anti­ 62. WOLF, U. (1979) XY gonadal dysgenesis and the gen status and segregation analysis. Hum. Genet. 58: H-Y antigen. Hum. Genet. 47: 269-277. 91-97. 63. WOLF, U. (1981) Genetic aspects of H-Y antigen. 52. SIMPSON, J.L.; BOMBARD, A.T.; MARTIN, A.O.; Hum. Genet. 58: 25-28. ELIAS, S. (1986) What are the clinical features of 64. WOLF, U.; FRACCARO, M.; MAYEROVA, A.; 45,X/46,XX mosaicism? In preparation. HECHT, T.; MARASCHIO, P.; HAMEISTER, H. 53. SIMPSON, J.L.; CHRISTAKOS, A.C.; HORWITH, (1980a) A gene controlling H-Y antigen on the X M.; SILVERMAN, F.S. (1971a) Gonadal dysgenesis chromosome. Hum. Genet. 54: 149-154. in individuals with apparently normal chromosomal 65. WOLF, U.; FRACCARO, M.; MAYEROVA, A.; complements: Tabulation of cases and compilation HECHT, T.; ZUFFARDI, O.; HAMEISTER, H. of genetic da.ta. Birth Defects 7 (6): 215-228. (1980b) patients are H-Y positive. 54. SIMPSON, J.L.; HORWITH, M.; MORILLO-CUCCI, Hum. Genet. 54: 315-318. G.; MCGOVERN, J.H.; LEVINE, MX.; GERMAN, J. 66. ZENZES, M.T.; WOLF, U.; ENGEL, W. (1978a) (1971b). Bilateral anorchia: Discordance in mono­ Organization in vitro of ovarian cells into testicular zygotic twins. Birth Defects, Orig. Artie. Ser. 7 (6): structures. Hum. Genet. 44: 333-338. 196-200. 67. ZENZES, M.T.; WOLF, U.; GUNTHER, E.; ENGEL, 55. STERNBERG, W.H.; BARCLAY, D.L.; KLOPFER, W. (1978b) Studies on the function of H-Y antigen. H.W. (1968) Familial XY gonadal dysgenesis. N. Dissociation and reorganization experiments on rat Engl. J. Med. 278: 695-700. gonadal cells. Cytogenet. Cell. Genet. 20: 365-372.