Familial Sex Reversal: A Review
Kyriakie Sarafoglou and
Harry Ostrer
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
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Introduction
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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.
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The Known Pathway for Testis Determination
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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).

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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).
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Familial True Hermaphroditism and XX Maleness
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True hermaphroditism is a distinct clinical entity based on the
histological findings of the gonads. True hermaphrodites contain both
ovarian and testicular gonadal tissue separately or, more commonly,
together as ovotestis. In contrast, XX males have only testes, and
their phenotype varies from normal male to a male with genital
ambiguity. Greater than 80% of the XX males have an SRY gene, almost
always transmitted as the result of an aberrant Y-to-X chromosomal
interchange (33). Like individuals with Klinefelter syndrome, these
males have small testes, but invariably, their stature is significantly
shorter. The majority of the XX males with genital ambiguity, such as
micropenis, hypospadias and cryptorchidism, do not have SRY genes (6).
The induction of testicular tissue in this subgroup of XX males
underlines the role of genes other than SRY that are involved in sex
determination.
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
).

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Figure 2. Pedigrees of familial 46,XX maleness
(left shading) and/or 46,XX true hermaphroditism
(right shading), sometimes coexisting in the same
pedigree.
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The pedigree where two second cousins were XX males suggested X-Y
interchange because both had Yp chromosomal markers in their genome
(pedigree 21) (36, 37). The next pedigree also show X-Y interchange,
through paternal transmission of an SRY-bearing X chromosome (pedigree
22) (38). The variability in the phenotype, one brother being 46,XX
true hermaphrodite and the other brother being XX male, was caused by
differential inactivation of the SRY-bearing X chromosome.
The possibility of autosomal recessive inheritance exist for the eight
pedigrees in which 46,XX siblings with true hermaphroditism have been
described (pedigrees 23 to 210) (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 23) (34).
A number of pedigrees have been described in which 46,XX true
hermaphrodites and 46,XX males coexist in the same family (pedigrees
211 to 214) (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
211) (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 213) (9). In another pedigree, two 46,XX brothers
had a 46,XX true hermaphrodite cousin and a 46,XX true hermaphrodite
uncle (pedigree 212) (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 212 and 213) (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 214) (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 215) (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 216) (49). Previous molecular analysis of XX males and true
hermaphrodites has not included gonadal tissue, and, thus, such models
have not been tested.
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Familial 46,XY Complete Gonadal Dysgenesis
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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).


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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.
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In all three pedigrees, the fathers carried the transmitted mutation
without being mosaic for wild-type SRY and mutant SRY alleles
(pedigrees 31 to 33) (51, 52, 53). Interestingly, the affected
individuals often share these mutant SRY genes with their
phenotypically normal brothers and paternal uncles. None of these
mutations has been found by population screening of large populations
normal of 46,XY males. However, the role of these mutations in gonadal
dysgenesis has been confirmed by biological assays. The mutation in the
first pedigree (190 M) reduced in vitro
DNA-binding activity of the SRY protein (51, 54). In the second
pedigree, the V60L mutation had negligible DNA-binding activity (53, 55). These mutations are, therefore, sex-reversing and not neutral
polymorphisms. It is more difficult to explain the mechanism of sex
reversal of the affected individuals of the third pedigree because the
inherited SRY mutation (F109S) had the same binding affinity as the
wild-type SRY (52). The effect of this mutation on bending DNA (another
function of SRY) was not tested. The differences of binding affinities
of the inherited mutations indicates the existence of other factors
that may influence the binding affinity of SRY in vivo.
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 34 to
36) (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
34) (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 35) (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 36) (58). Paternal mosaicism at the
gonadal level was responsible for 46,XY gonadal dysgenesis in two
siblings with SRY gene deletion (pedigree 37) (60). The fathers
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 38) (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 39) (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
310 to 312) (63, 64, 65). All five affected individuals in one pedigree
had gonadoblastoma, with the youngest affected individuals being 6
months of age (pedigree 311) (65). Similarly, one of four, two of
three affected individuals in the other pedigrees had gonadoblastoma
(pedigrees 310 and 312) (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 313) (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 314) (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 315) (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 316) (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 317) (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.
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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 814 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
1214 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 41) (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 42 to 44) (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 42) (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 43) (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 44), 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, 45) (77). The possibility of an X-linked
gene was suggested by the pedigree (pedigree 46) 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 47) 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 48) (79). A pedigree (pedigree 49) 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).

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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.
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Discussion
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This review of the literature demonstrates that many cases of sex
reversal are familial, rather than sporadic. Sometimes the effect on
the phenotype can be so mild that the unsuspecting clinician may not
diagnose the mildly affected individuals until a more severe affected
family member seeks medical attention. Detailed family history should
be taken for individuals with sex reversal, and siblings should be
examined. In addition to cytogenetic and hormonal analysis (sex
steroids, LH, FSH, and LHRH or HCG stimulation tests, if appropriate),
evaluation of any suspected cases should include gonadal biopsy.
Special considerations may apply to individuals with specific forms of
sex reversal. 46,XX males may actually be true hermaphrodites and
should be carefully reassessed at onset of puberty before development
of gynecomastia. Testicular biopsy at that time would offer definite
diagnosis. Newly diagnosed cases may be the result of an inherited
mutation, and, if found, careful examination and screening should be
offered to all family members.
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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