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Familial Sex Reversal: A Review

Human Genetics Program, Department of Pediatrics, New York University School of Medicine, New York, New York 10016

Address correspondence and requests for reprints to: Dr. Harry Ostrer, Human Genetics Program, Department of Pediatrics, 550 First Avenue, MSB 136, New York, New York 10016. E-mail: harry.ostrer{at}med.nyu.edu

	Introduction

Top Introduction The Known Pathway for... Familial True Hermaphroditism... Familial 46,XY Complete Gonadal... Familial Partial Gonadal... Discussion References

 
Since 1905, it has been recognized that a gene on the Y chromosome, originally termed TDF (for "testes-determining factor") acted in a dominant fashion to promote male sexual development (1). In 1990, the SRY (sex-determining region Y) gene was identified as TDF (2). This gene was cloned, and its identity was confirmed by studying individuals with sex reversal (phenotypic sex of one type, genetic sex of the other). Subsequent studies of sex-reversed individuals have shown that this gene is neither necessary nor sufficient to promote testis development (3, 4, 5, 6, 7, 8, 9, 10).

This review will highlight the many observed cases of sex-reversal that have led to the identification of genes other than SRY that promote testicular development and that have suggested a rudimentary genetic pathway. However, rather than focusing on work that has been well-summarized in other reviews, this article will delve into the analysis of cases of sex reversal that are likely to be informative for identifying new genes in the testis-determining pathway (11, 12, 13). These cases fall into two categories; either they are associated with novel genetic syndromes or they are familial, with multiple affected individuals within a pedigree. The frequent occurrence of familial sex-reversal suggests that family members other than the proband may be at risk for sex reversal themselves or for having offspring with sex reversal.

	The Known Pathway for Testis Determination

Top Introduction The Known Pathway for... Familial True Hermaphroditism... Familial 46,XY Complete Gonadal... Familial Partial Gonadal... Discussion References

 
Mapping and cloning of the responsible genes for sex reversal is not always an easy task. The keys for identifying the known genes have been either the presence of chromosomal rearrangements in some cases that give clues as to their location or the association with known malformation or tumor syndromes, whose causative genes were cloned using other molecular techniques. The genetic basis of many familial cases of 46,XY and 46,XX sex reversal is unknown. Linkage studies of pedigrees with familial sex reversal should aid in the identification of new sex-determining genes.

In humans and other mammals, sex determination generally proceeds in the direction of female development unless genes involved in testis determination are activated. The SRY gene has a fundamental role in sex determination and is believed to be the switch that initiates the testis development. SRY is regulated by genes upstream in the sex determination pathway and exerts its function by interaction with genes downstream in the pathway. Any deregulation of the sex pathway leads to abnormal sex differentiation and, in some cases, to complete sex reversal (Fig. 1). The identification and cloning of SRY depended on the investigation of patients with sex reversal syndromes, some with chromosomal rearrangements. In addition to SRY, autosomal and X-linked loci have also been linked with failure to develop a testis and, thus, sex reversal (14, 15) (Fig. 1). The first autosomal gene that was found to have a role in testis determination was the Wilms’ tumor suppressor (WT1), originally identified by positional cloning using DNA from familial cases of Wilms’ tumor having a deletion of the short arm of chromosome 11 (16). Mutations in this gene were shown to be associated with sex reversal (46,XY gonadal dysgenesis) along with bilateral Wilms’ tumor and diffuse mesangial sclerosis, all hallmarks of Denys-Drash syndrome (17, 18). Likewise, different mutations in this gene have been observed in Frasier syndrome, a condition of nonspecific focal and segmental glomerular sclerosis without Wilms’ tumor, and 46,XY gonadal dysgenesis, usually presenting with gonadoblastoma (19). The second autosomal gene that was found to have a role in testis determination was SOX9. Mutations in this gene are associated with campomelic dysplasia (CD), a skeletal malformation syndrome in which the 46, XY individuals commonly have sex reversal (20). The positional mapping and cloning of SOX9 was facilitated by the identification of balanced translocations involving the long arm of chromosome 17 in individuals with CD and sex reversal (21, 22, 23). Recently, mutation in the SF-1 gene was identified as the cause in a patient with primary adrenal failure and 46,XY gonadal dysgenesis (24). Other autosomal loci on chromosomes 2q, 9p, and 10q have been implicated because some individuals with deletions of these chromosomal regions are 46,XY females (25, 26, 27, 28). X chromosomal loci have also been implicated to play a role in sex reversal. Analysis of sex-reversed subjects with duplications of Xp chromosome led to the mapping of dosage sensitive sex reversal (DSS) locus (29, 30, 31). This locus maps to a 160-kb region of Xp21. When duplicated, this locus causes testicular regression even in presence of intact SRY; deletion of this region does not have an effect on testis determination, suggesting that DSS is not ordinarily a sex-determining gene. Another X-linked gene, XH2, was found to have a role in testicular development when a subject with thalassemia, mental retardation, and sex reversal was shown to have a mutation in this gene (32).

View larger version (21K): [in this window] [in a new window]   Figure 1. A pathway showing known genes and chromosomal regions in the testis-determining pathway. A, Translocations of SRY are known to be associated with 80% of cases of 46,XX maleness. B, Mutations in the SRY, SOX9, SF1, and WT1 genes are associated with 46,XY gonadal dysgenesis, as are deletions of chromosome 2q, 9p, and 10q, and duplication of chromosome Xp21. Mutations in some of these genes are associated with more complicated phenotypes, including CD (SOX9), adrenal failure (SF1), and Denys-Drash and Frasier syndromes (WT1).

	Familial True Hermaphroditism and XX Maleness

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The histology of testicular tissue is identical in 46,XX males and XX true hermaphrodites with normal spermatogonia in the youngest patients and dysgenetic tissue without spermatogonia after 5 or 8 yr of age (34). The majority of cases of 46,XX maleness and true hermaphroditism occur sporadically (33, 35); however, there are cases of true hermaphrodites and 46,XX males coexisting within the same families with all affected individuals ascertained on the basis of genital ambiguity. The majority of familial cases are SRY negative, and, thus, the mode of inheritance has not yet clarified (3, 4, 6). Analysis of several reported pedigrees show evidence of different modes of inheritance (Fig. 2 and Table 1).

View larger version (43K): [in this window] [in a new window]   Figure 2. Pedigrees of familial 46,XX maleness (left shading) and/or 46,XX true hermaphroditism (right shading), sometimes coexisting in the same pedigree.

The possibility of autosomal recessive inheritance exist for the eight pedigrees in which 46,XX siblings with true hermaphroditism have been described (pedigrees 2–3 to 2–10) (34, 39, 40, 41, 42, 43, 44, 45). No parental consanguinity has been described in these families. The alternative hypothesis is sex-limited autosomal dominant transmission with the carrier fathers being nonpenetrant for the XY male phenotype. The pedigree where both 46,XX brothers have strabismus and nystagmus, as does their father, supports such a model (pedigree 2–3) (34).

A number of pedigrees have been described in which 46,XX true hermaphrodites and 46,XX males coexist in the same family (pedigrees 2–11 to 2–14) (7, 9, 46, 47). These familial cases, where XX true hermaphrodites coexist with XX males in the same sibship, provide evidence to support the hypothesis that these disorders are alternative manifestations of the same genetic defect with marked variability in the expression and penetrance of the mutant gene. An autosomal dominant mutation with incomplete penetrance or an X-linked mutation limited by the presence of the Y chromosome could explain the induction of the testicular tissue in the absence of SRY. In one pedigree, a 46,XX true hermaphrodite with genital ambiguities had one 46,XX brother who was also ambiguous, a normal 46,XX sister, and a 46,XY brother (pedigree 2–11) (46). In contrast, the uncle was a 46,XX male with normal male phenotype. In a similar pedigree, a 46,XX true hermaphrodite and his 46,XX brother had an XX true hermaphrodite uncle, all with genital ambiguity (pedigree 2–13) (9). In another pedigree, two 46,XX brothers had a 46,XX true hermaphrodite cousin and a 46,XX true hermaphrodite uncle (pedigree 2–12) (47) (although both 46,XX males have since been shown to be true hermaphrodites). All affected individuals had genital ambiguity. Analysis of these two pedigrees using molecular markers did not support a Y-to-X interchange model or other mechanism involving the SRY gene (pedigrees 2–12 and 2–13) (3, 9).

Instead, these pedigrees all support a model in which up-regulated autosomal or X-linked testis-determining gene (or a down-regulated silencer gene) is transmitted through a carrier 46,XY male and demonstrates a threshold effect. Those for whom the threshold is exceeded are 46,XX males, whereas the other 46,XX carriers are true hermaphrodites. Not all pedigrees demonstrate such sex-limited transmission via carrier males. Paternal and maternal transmission of the defect occurred in the pedigree where a 46,XX true hermaphrodite had two affected first cousins (pedigree 2–14) (7). One cousin was a 46,XX true hermaphrodite, and his sibling was a 46,XX male. Both true hermaphrodites had genital ambiguity. Parental consanguinity was denied, although the origin of this family in rural Malaysia was supportive of the possibility of an autosomal recessive testis-determining gene that was up-regulated in 46,XX individuals and showed a threshold effect.

Another possibility for the coexistence of the XX males and true hermaphrodites within the same family may be explained on the basis of inheritance of genes that predispose to chimerism. Many cases of sporadic true hermaphroditism have been shown to be on the basis of chimerism of 46,XX and 46,XY zygotes. In one pedigree, a mosaic 46,XX/XY hermaphrodite had a 46,XX brother (pedigree 2–15) (48). The proportion of 46,XY-bearing cells in the gonad may have been so great that the gonad of the 46,XX male was a testis. Gonadal mosaicism can be implied for the pedigree where two brothers are 46,XX true hermaphrodites with male phenotype, one carrying a paternally transmitted marker, possibly of Y chromosomal origin and the other not (pedigree 2–16) (49). Previous molecular analysis of XX males and true hermaphrodites has not included gonadal tissue, and, thus, such models have not been tested.

	Familial 46,XY Complete Gonadal Dysgenesis

Top Introduction The Known Pathway for... Familial True Hermaphroditism... Familial 46,XY Complete Gonadal... Familial Partial Gonadal... Discussion References

 
Individuals affected with 46,XY complete gonadal dysgenesis lack testicular development and present with streak gonads, well-developed Mullerian structures, absent Wolffian structures, and female phenotype. Because no other somatic abnormalities are present, they are usually not diagnosed until puberty, when they present with absence of secondary sexual characteristics and amenorrhea.

Genetically, complete 46,XY gonadal dysgenesis is a very heterogeneous disorder with both Y-linked and non-Y-linked forms. Eighty percent of patients with sporadic or familial 46,XY gonadal dysgenesis do not have a mutation or deletion of the SRY gene, indicating that other autosomal or X-linked genes have a role in sex determination. Whereas the majority of the cases occur sporadically, there are several reports of pedigrees with familial transmission of the disorder (Fig. 3 and Table 2). One would not expect a Y-linked form of familial 46,XY dysgenesis because affected 46,XY individuals are usually sterile females and, thus, unable to pass on the mutant gene. Yet, one third of the described SRY mutations are inherited (50).

View larger version (60K): [in this window] [in a new window]   Figure 3. Pedigrees of familial 46,XY pure gonadal dysgenesis (•). Male carriers of SRY mutations are shown by right shading. Siblings affected with similar nongonadal phenotypes are shown by dots within the circles, and individuals who were diagnosed with gonadoblastoma are marked with asterisks.

The variable penetrance of the inherited SRY mutations associated with defined phenotypes of either XY female with complete gonadal dysgenesis or normal fertile male without ambiguous genitalia or infertility is puzzling. A model proposed in mice, where the ability of the Tdy to induce testis formation depends on particular alleles at autosomal loci may have an analogy and explain the mechanism for the above cases (56).

Less puzzling are the familial cases of 46,XY gonadal dysgenesis for which the father has mosaicism for an SRY mutation (pedigrees 3–4 to 3–6) (57, 58, 59). In the first pedigree, three 46,XY females inherited the P125L SRY mutation from their phenotypically normal, fertile father, who was mosaic in his blood (and presumably testis) (pedigree 3–4) (57). This mutation was also shown to reduce the DNA binding of the SRY protein. Likewise, decreased binding was demonstrated for the 97C-T nonsense mutation that resulted to a truncated SRY polypeptide with decreased DNA binding (pedigree 3–5) (59). In the third pedigree, a missense 609T-G mutation in the two probands that was mosaic in their father was not tested for its effect on DNA binding by the encoded protein (pedigree 3–6) (58). Paternal mosaicism at the gonadal level was responsible for 46,XY gonadal dysgenesis in two siblings with SRY gene deletion (pedigree 3–7) (60). The father’s peripheral blood was SRY positive and showed no mosaicism.

Evidence for an X-specific gene involved in sex determination was first postulated after the identification of a family with three phenotypic 46,XY females in three different sibships related via the maternal line (pedigree 3–8) (61). Later, another pedigree demonstrated five phenotypic 46,XY females in three different sibships and with a similar mode of transmission of the disorder (pedigree 3–9) (62). The proposita of this sibship was diagnosed at 21 yr of age. This led to the diagnosis of her eldest sisters and the two younger nieces. Because of the delay in the diagnosis, all three sisters had osteoporotic bones. Other pedigrees have a similar mode of transmission (pedigrees 3–10 to 3–12) (63, 64, 65). All five affected individuals in one pedigree had gonadoblastoma, with the youngest affected individuals being 6 months of age (pedigree 3–11) (65). Similarly, one of four, two of three affected individuals in the other pedigrees had gonadoblastoma (pedigrees 3–10 and 3–12) (63, 64). Although in all these pedigrees an X-linked recessive mode of inheritance is likely because of the apparent absence of male-to-male transmission, a sex-limited autosomal dominant mode of inheritance affecting only XY individuals could not be ruled out. One pedigree with duplication of Xp21, including the DSS region, demonstrates how such an X-linked mechanism might work (pedigree 3–13) (30). In this pedigree, inheritance of DSS locus resulted in familial sex reversal of the 46,XY affected individuals. None of the affected individuals in the other pedigrees was analyzed for the Xp21 duplication.

An autosomal recessive mode of inheritance has been postulated as another mechanism for 46,XY sex reversal because of the rate of affected individuals— 28.6% in one pedigree (pedigree 3–14) (66) or by virtue of the association of the association of 46,XY gonadal dysgenesis with other syndromic features. In one pedigree, both affected siblings had recessive chondrodysplasia and dysmorphic features; however, the sibling with 46,XX karyotype had normal ovaries, but the one with 46,XY karyotype was a phenotypic female with streak gonads (pedigree 3–15) (67). Another pedigree supported autosomal recessive mode of inheritance of 46,XY gonadal dysgenesis because of consanguinity. The affected individuals had spastic paraplegia, optic atrophy, and microcephaly with normal intelligence. The sibling with the 46,XY karyotype had normal female external genitalia and streak gonads (pedigree 3–16) (10). Like other previously described cases of syndromic sex reversal, these pedigrees demonstrate that the sex-determining gene may be pleiotropic in their effects, causing changes not only in gonads, but also in other tissue, as well. Although autosomal recessive inheritance is presumed for the pedigrees, parental germline mosaicism for an autosomal dominant condition cannot be excluded.

One pedigree is illustrative of this point (pedigree 3–17) (68). This pedigree had familial sex reversal because of paternal germ cell mosaicism for a mutant SOX9 gene. It is interesting that the same mutation (insertion C at position 1096 in exon 3) resulted in different gonadal phenotypes in the two 46,XY affected siblings. The proband had bilateral ovotestis as gonads, whereas the other sibling had ovaries at 19 weeks gestational age.

	Familial Partial Gonadal Dysgenesis and Embryonic Testicular Regression Syndrome

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The term "partial gonadal dysgenesis" has been used to describe individuals who have partial testis determination, dysgenetic gonads, a mix of Mullerian and Wolffian structures, and ambiguous genitalia. Other terms used to describe this syndrome are "mixed gonadal dysgenesis" or "dysgenetic male pseudohermaphroditism." It is regarded as part of the clinical spectrum of 46,XY gonadal dysgenesis. The gonadal histology of patients with 46,XY partial gonadal dysgenesis consists of poorly formed seminiferous tubules in combination with ovarian-like stroma. Gonads can be dysgenetic in one side and normal testis on the other side or dysgenetic bilaterally.

"Embryonic testicular regression syndrome" is a term used to describe the spectrum of genital anomalies resulting from regression of testis development from 8–14 weeks of gestation. For example, if the regression of the fetal testes occurs between the 8 and 10 weeks of gestation, the individual may have complete absence of gonads, rudimentary Mullerian and/or Wolffian ductal structure, hypoplastic uterus, and female genitalia with/or without ambiguity. This condition has been referred as true agonadism or gonadal agenesis. Regression of the testes after the critical period of male differentiation (around 12–14 weeks), results in anorchia, where the individual has male internal and external genitalia. Partial testicular regression after the critical period would result to a male phenotype as in anorchia but with small rudimentary testes (69).

The etiology of either of the above syndromes is very heterogeneous. Some of the subjects with 46,XY partial gonadal dysgenesis seem to have autosomal abnormalities. Sporadic cases of partial gonadal dysgenesis have been described with mutations of the WT1 genes and deletions of 9p and 10q chromosomes (25, 28, 70, 71). Only two SRY mutations, a de novo deletion 3' to the SRY-ORF and a missense mutation 5' to SRY-ORF, have been found in two subjects with sporadic partial gonadal dysgenesis (72, 73). The causes of the vast majority of cases of partial gonadal dysgenesis or embryonic testicular regression are unknown.

Analysis of families (listed below) with several affected individuals with either 46,XY partial gonadal dysgenesis or embryonic testicular regression syndrome implicate X-linked, autosomal recessive, or autosomal dominant inheritance (Fig. 4 and Table 3). The first described pedigree had two agonadic 46,XY siblings with marked phenotypic variability (pedigree 4–1) (74). One sibling had normal female phenotype, and the other was a male with ambiguous genitalia. Three pedigrees suggested autosomal recessive inheritance on the basis of parental consanguinity (pedigrees 4–2 to 4–4) (8, 75, 76). The first pedigree had three 46,XY siblings with testicular regression and a normal female phenotype and a fourth 46,XY sibling with rudimentary testes syndrome, male phenotype, azoospermia, and atrophic testes (pedigree 4–2) (76). The parents were first cousins. The second pedigree had two agonadic sisters, one with 46,XY karyotype and the other one with 46,XX (pedigree 4–3) (8). This pedigree highlights the coexistence of gonadal agenesis in 46,XX and 46,XY individuals in the same family. Such cases demonstrate the likelihood of genes upstream of SRY that mediate the development of the undifferentiated gonadal ridge. In the third pedigree (pedigree 4–4), the two 46,XY agonadic sisters had mental retardation and unusual facies (75). The elder sister also had renal agenesis and malrotation of the colon. These parents were also first cousins. Autosomal gene involvement is also suggested by the next pedigree where gonadal agenesis coexists with several somatic abnormalities (pedigree, 4–5) (77). The possibility of an X-linked gene was suggested by the pedigree (pedigree 4–6) in which the mothers of the affected 46,XY siblings with rudimentary testes syndrome were sisters and nonconsanguineous with their spouses (69). A kindred with partial gonadal dysgenesis (pedigree 4–7) was negative for linkage to WT1, SOX9, DSS, implicating other, unidentified autosomal or X-linked genes (5, 78). The mechanism for partial gonadal dysgenesis in the family with three siblings with partial gonadal dysgenesis has not been identified (pedigree 4–8) (79). A pedigree (pedigree 4–9) in which one sister has 46,XY gonadal dysgenesis and the other one partial gonadal dysgenesis implicates a common genetic mechanism for these two disorders (80).

View larger version (31K): [in this window] [in a new window]   Figure 4. Pedigrees of 46,XY gonadal agenesis (•), rudimentary testes or anorchia (right diagonal shading), partial gonadal dysgenesis (horizontal shading), or hypospadias (shading in upper right corner). Stillbirths are shown as small, dark circles.

	Discussion

Top Introduction The Known Pathway for... Familial True Hermaphroditism... Familial 46,XY Complete Gonadal... Familial Partial Gonadal... Discussion References

46,XY reversed individuals with partial or complete gonadal dysgenesis at high risk to develop gonadal tumors, such as gonadoblastoma/dysgerminoma. There is a direct relationship between Y-linked genes and tumor development in dysgenetic gonads. The risk of malignancy is estimated to be about 30% and is not confined only to phenotypic female siblings, but extends to phenotypic male siblings with the disorder (81). It is also important to diagnose these patients early because they may not go in to puberty on their own, or if they have mixed gonadal dysgenesis, genital ambiguity may worsen at the time of puberty. The other major medical reason for early and correct diagnosis of gonadal dysgenesis is prevention of osteoporosis later in life because of the estrogen deficiency during puberty, the critical period of bone development.

The mechanism of familial sex reversal seems to be due to SRY mutations, mutations in autosomal or X-linked genes, and gonadal mosaicism or chimerism for a Y chromosome-bearing cell line. As has been shown for SRY and for other sex-determining genes, such as SOX9, WT1 SF-1, and XH2, there is phenotypic variability associated with different mutations. As a guide for identifying new genes, presence of syndromic features may be suggestive of mutation in a known gene. Preliminary linkage studies demonstrate that other genes, the identities of which have not yet been established, are likely to play a role (78). Genetic analysis of all these families could help in the identification of novel genes involved in sex determination and their linear array in a regulatory cascade.

Received April 15, 1999.

Revised November 4, 1999.

Accepted November 19, 1999.

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Top Introduction The Known Pathway for... Familial True Hermaphroditism... Familial 46,XY Complete Gonadal... Familial Partial Gonadal... Discussion References

 

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