0021-972X/00/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 2
Printed in U.S.A.
CLINICAL REVIEW 111
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
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 (3–10).
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 (11–13). 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.
less 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 (21–23). 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 (25–28). 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 –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
The Known Pathway for Testis Determination
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 unReceived April 15, 1999. Revision received November 4, 1999.
Accepted November 19, 1999.
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@
med.nyu.edu.
483
484
SARAFOGLOU AND OSTRER
FIG. 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).
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).
Familial True Hermaphroditism and XX Maleness
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
JCE & M • 2000
Vol 85 • No 2
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).
The pedigree where two second cousins were XX males
suggested X-Y interchange because both had Yp chromosomal markers in their genome (pedigree 2–1) (36, 37). The
next pedigree also show X-Y interchange, through paternal
transmission of an SRY-bearing X chromosome (pedigree
2–2) (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 SRYbearing 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 2–3 to 2–10)
(34, 39 – 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,
CLINICAL REVIEW
485
FIG. 2. Pedigrees of familial 46,XX
maleness (left shading) and/or 46,XX
true hermaphroditism (right shading),
sometimes coexisting in the same pedigree.
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
Individuals affected with 46,XY complete gonadal dysgenesis lack testicular development and present with streak
gonads, well-developed Mullerian structures, absent Wolf-
486
SARAFOGLOU AND OSTRER
JCE & M • 2000
Vol 85 • No 2
FIG. 3. Pedigrees of familial 46,XY
pure gonadal dysgenesis (F). 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.
fian 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-Ylinked 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).
In all three pedigrees, the fathers carried the transmitted
mutation without being mosaic for wild-type SRY and mutant SRY alleles (pedigrees 3–1 to 3–3) (51–53). 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 poly-
CLINICAL REVIEW
487
FIG. 3b.
morphisms. 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 3– 4 to 3– 6) (57–59). 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
488
SARAFOGLOU AND OSTRER
JCE & M • 2000
Vol 85 • No 2
FIG. 4. Pedigrees of 46,XY gonadal
agenesis (F), 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.
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– 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
CLINICAL REVIEW
489
TABLE 1. Familial cases of 46,XX maleness and/or true hermaphroditism
Pedigree
2-1, De La Chapelle et
al. (1977); Page (1985)
2-2, Abbas et al. (1993)
2-3, Toublanc et al.
(1993)
2-4, Manouvier et al.
(1985) (2 families)
Phenotype of 46,XX affected individual
Two second cousin are 46,XX males with
gynecomastia and small testes. Distant cousin is
similarly affected
Two brothers; one is a 46,XX true hermaphrodite
and the other is a 46,XX male
Two sibling 46,XX males with genital ambiguity.
Both have strabismus and nystagmus as does
their father
a) Two siblings with 46,XX true hermaphroditism,
ambiguous genitalia and female phenotype
b) Two siblings with 46,XX true hermaphroditism,
ambiguous genitalia and female phenotype
2-5, Milner et al. (1958)
2-6, Fraccaro et al.
(1979)
2-7, Gallegos et al.
(1976)
2-8, Mori et al. (1968)
2-9, Armendares (1975)
2-10, Clayton et al.
(1962)
2-11, Kasdan et al.
(1973)
2-12, Skordis et al.
(1987)
2-13, Ramos (1996)
2-14, Kuhnle et al.
(1993)
2-15, Berger (1969)
2-16, Borges et al.
(1963)
Two siblings with 46,XX true hermaphroditism and
male phenotype, one with small testes,
cryptorchidism and gynecomastia, the other with
penoscrotal hypospadias and chordee
Two siblings with 46,XX true hermaphroditism, one
with female phenotype, penoscrotal hypospadias
and cryptorchidism, and the other with a male
phenotype, perineal hypospadias and
gynecomastia
Three siblings with 46,XX true hermaphroditism,
male phenotype, grade III hypospadias and
gynecomastia
Two siblings with 46,XX true hermaphroditism,
ambiguous genitalia and female phenotype
Three siblings with 46,XX true hermaphroditism
and male phenotype with ambiguous genitalia,
including hypospadias, bifid scrotum, and
gynecomastia during puberty
Three siblings with 46,XX true hermaphroditism
and male phenotype. Two had penoscrotal
hypospadias and cryptorchidism. Two developed
gynecomastia at puberty
Propositus is a 46,XX true hermaphrodite with
urogenital sinus and male phenotype. One sibling
is 46,XX male with penoscrotal hypospadias and
chordee. The paternal uncle is an 46,XX male
Propositus is 46,XX true hermaphrodite with male
phenotype, penoscrotal hypospadias, small penis
and bifid scrotum. Niece is a 46,XX true
hermaphrodite with female phenotype urogenital
sinus, absence of labia minora and clitoromegaly.
Two of his nephews are 46,XX males with male
phenotype and genital abnormalities, similar to
their uncle’s
Propositus is a 46,XX, true hermaphrodite with
penoscrotal hypospadias and micropenis. His uncle
is 46,XX true hermaphrodite male with
hypospadias. Another sibling is 46,XX male with
cryptorchidism
Proposita is a 46,XX true hermaphrodite with
female phenotype and urogenital sinus with
clitoromegaly. Two cousins are a 46,XX true
hermaphrodite with female phenotype and the
same genital abnormalities and a 46,XX male with
normal male phenotype except for small testes
One sibling is 46,XX/46,XY female true
hermaphrodite with virilization and the other is a
46,XX male
One sibling 47,XX, ⫹mar true hermaphrodite with
normal male phenotype except for chordee. The
other is a 46,XX true hermaphrodite with a male
phenotype and ambiguous genitalia
Mode of inheritance
Fathers are carriers of a
balanced Yp-X
translocation
Father harbors two copies
of SRY, one on his Y
chromosome and one on
his X chromosome
X-linked? Sex-limited,
autosomal dominant?
Autosomal recessive?
X-linked? Sex-limited,
autosomal dominant?
Autosomal recessive?
X-linked? Sex-limited,
autosomal dominant?
Autosomal recessive?
X-linked? Sex-limited,
autosomal dominant?
Autosomal recessive?
Genetic abnormality
Yp-X interchange
SRY-X
translocation
Unknown
Unknown
Unknown
Unknown
X-linked? Sex-limited,
autosomal dominant?
Autosomal recessive?
Unknown
X-linked? Sex-limited,
autosomal dominant?
Autosomal recessive?
X-linked? Sex-limited,
autosomal dominant?
Autosomal recessive?
X-linked? Sex-limited,
autosomal dominant?
Autosomal recessive?
Unknown
X-linked? Sex-limited,
autosomal dominant?
Autosomal recessive?
Unknown
X-linked? Sex-limited,
autosomal dominant?
Unknown
X-linked? Sex-limited,
autosomal dominant?
Unknown
X-linked? Sex-limited,
autosomal dominant?
Unknown
X-linked? Sex-limited,
autosomal dominant?
Unknown
X-linked? Sex-limited,
autosomal dominant?
Autosomal recessive?
Paternal transmission of a
marker chromosome with
Y material
46,XX/46,XY
mosaicism at the
gonadal level?
46,XX/46,XX ⫹mar
mosaicism at the
gonadal level?
Unknown
Unknown
490
JCE & M • 2000
Vol 85 • No 2
SARAFOGLOU AND OSTRER
TABLE 2. Familial cases of 46,XY gonadal dysgenesis
Pedigree
3-1, Hawkins et al.
(1992)
3-2, Jager et al. (1992)
3-3, Vilain et al. (1992)
3-4, Schmitt-Ney et al.
(1995) (2 families)
Phenotype of 46,XY affected individual
Mode of inheritance
Proposita is a female with gonadal dysgenesis.
Father and one brother are fertile male carriers
Proposita is a female with gonadal dysgenesis.
Father, paternal uncle and two brothers are
fertile male carriers
Proposita, one sibling, and paternal aunt are
females with gonadal dysgenesis. Father and
paternal uncle are fertile male carriers
a) Proposita, one sibling and one half-sibling are
females with gonadal dysgenesis
b) Proposita is a female with gonadal dysgenesis
3-5, Bilbao et al.
(1996)
Two siblings are females with gonadal dysgenesis
3-6, Hines et al. (1997)
Proposita and one sibling are females with gonadal
dysgenesis
Two siblings are females with gonadal dysgenesis
3-7, Barbosa et al.
(1995)
3-8, Steinberg et al.
(1968)
3-9, Espiner et al.
(1970)
3-10, German et al.
(1978)
3-11, Mann et al.
(1983)
3-12, Boczowski et al.
(1976)
3-13, Bernstein et al.
(1980)
3-14, Berg et al. (1983)
3-15, Nivelon et al.
(1992)
3-16, Teebi et al.
(1997)
3-17, Cameron et al.
(1996)
Proposita, maternal cousin, and maternal aunt are
females with gonadal dysgenesis. The proposita
had microscopic focus of gonadoblastoma in one
of her gonads
Proposita, two siblings and two maternal nieces
are females with gonadal dysgenesis
Proposita, sibling, maternal aunt and niece are
females with gonadal dysgenesis. One had
gonadoblastoma
Proposita, two siblings, maternal aunt and
maternal second cousin are females with gonadal
dysgenesis. All five had gonadoblastoma
Proposita and two siblings are females with
gonadal dysgenesis. Both siblings had
gonadoblastoma
Proposita and one sibling are females with gonadal
dysgenesis
Proposita and one sibling are females with gonadal
dysgenesis. Both had gonadoblastoma
Both siblings are female, one with gonadal
dysgenesis. Syndromic features include
chondrodysplasia, microcephaly, coloboma of the
optic disc. Parents were not related
Both siblings are female, one with gonadal
dysgenesis (unknown in the other). Syndromic
features include spastic paraplegia, microcephaly
and optic atrophy
Proposita is a true hermaphrodite with ambiguous
genitalia and CD. The two other siblings affected
with CD are 46,XY and 46,XX females with
ovaries
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
Y-linked
Y-linked
Y-linked
Y-linked
Y-linked; father is mosaic
for wild-type and
mutant SRY alleles
Y-linked; father is mosaic
Y-linked; father is mosaic
Y-linked; father is mosaic
Genetic abnormality
SRY mutation (I90M), causing
decreased binding.
SRY mutation (F109S), causing
normal binding but bending
of DNA has not been tested
SRY mutation (V60L), causing
decreased binding
SRY mutation (P125L), causing
decreased binding
SRY mutation (S91G), causing
decreased binding
SRY mutation 97C-T causing
truncated SRY protein with
decreased binding
Missence SRY mutation (T➪G
at 609)
SRY gene deletion
Y-linked; father probably
has germ-line
mosaicism
Unknown
X-linked recessive?
Unknown
X-linked recessive?
Unknown
X-linked recessive?
Unknown
Autosomal or X-linked
recessive?
Unknown
Autosomal or X-linked
recessive?
Autosomal or X-linked
recessive?
Autosomal or X-linked
recessive?
Xp21 duplication
Unknown
Unknown
Autosomal or X-linked
recessive?
Unknown
Autosomal dominant
SOX9 gene mutation
(1096insC)
ovotestis as gonads, whereas the other sibling had ovaries at
19 weeks gestational age.
Familial Partial Gonadal Dysgenesis and Embryonic
Testicular Regression Syndrome
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
CLINICAL REVIEW
491
TABLE 3. Familial cases of 46,XY partial gonadal dysgenesis and/or testicular hypoplasia
Pedigree
4-1, Josso (1980)
4-2, Naffah (1989)
4-3, Mendoca (1994)
4-4, Kennerknecht
(1995)
4-5, Verloes (1990)
4-6, Aquafredda
(1987)
4-7, Fechner (1993)
4-8, Phansey (1980)
4-9, Barr (1967)
Genetic
abnormality
Phenotype of 46,XX affected individual
Mode of inheritance
Proposita has anorchia and is a 46,XY male with micropenis
and cryptorchidism. The sibling is a 46,XY agonadic female
with urogenital sinus, absent uterus and coexisting Mullerian
and Wolffian structures
Proposita and two other siblings are 46,XY agonadic females.
One brother is azoospermic with atrophic testicles
(rudimentary testes syndrome). Parents are consanguineous
Proposita, a 46,XY female, and a 46,XX female sibling are
agonadic. Parents are consanguineous
Proposita is a 46,XY agonadic female with facial dysmorphism,
mental retardation, malrotation of the colon and absence of
right kidney and ureter. The sibling is 46,XY agonadic female
and shares the same anomalies, but has both kidneys. The
parents are consanguineous
The proposita is a 46,XY agonadic male with BorjesonForssman-Lehman-like syndrome and ambiguous genitalia.
The sibling has similar anomalies and is a 46,XY agonadic
female
Two cousins are 46,XY males with micropenis and small testes
due to rudimentary testes syndrome. Their mothers are
sisters
Proposita and two or her mother’s siblings are 46,XY females
with partial gonadal dysgenesis and virilization. One of her
siblings and one of her mother’s are 46,XY males with partial
gonadal dysgenesis and sexual ambiguity
Proposita and two siblings are 46,XY females with partial
gonadal dysgenesis. One sibling had gonadoblastoma and the
other sibling and the proposita had clitoromegaly
Proposita is a 46,XY female with partial gonadal dysgenesis
and virilization. The other sibling is a 46,XY female with
pure gonadal dysgenesis (or agenesis). The nephew has
hypospadias, but gonads were not examined
X-linked? Autosomal
dominant? Autosomal
recessive?
Unknown
Autosomal recessive?
Unknown
Autosomal recessive?
Unknown
Autosomal recessive?
Unknown
X-linked? Autosomal
dominant? Autosomal
recessive?
Unknown
X-linked recessive?
Unknown
X-linked recessive? Sexlimited autosomal
dominant?
Unknown
X-linked? Sex-limited
autosomal dominant?
Autosomal recessive?
X-linked? Sex-limited
autosomal dominant?
Autosomal recessive?
Unknown
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
Unknown
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
492
JCE & M • 2000
Vol 85 • No 2
SARAFOGLOU AND OSTRER
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).
Discussion
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 chromosomebearing 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.
References
1. Wilson EB. 1911 The sex chromosomes. Arch Mikrosk Anat Enwicklungsmech. 77:249 –271.
2. Sinclair AH, Berta P, Palmer MS, et al. 1990 A gene from the human sexdetermining region encodes a protein with homology to a conserved DNAbinding motif. Nature. 346:240 –244.
3. Ostrer H, Wright G, Clayton M, Skordis N, MacGillivray MH. 1989 Familial
XX chromosomal maleness does not arise from a Y chromosomal translocation.
J Pediatr. 114:977–982.
4. Abbas NE, Toublanc JE, Boucekkine C, et al. 1990 A possible common origin
of “Y-negative” human XX males and XX true hermaphrodites. Hum Genet.
84:356 –360.
5. Fechner PY, Marcantonio SM, Ogata T, et al. 1993 Report of a kindred with
X-linked (or autosomal dominant sex-limited) 46,XY partial gonadal dysgenesis. J Clin Endocrinol Metab. 76:1248 –1253.
6. Ferguson-Smith MA, Cooke A, Affara NA, Boyd E, Tolmie JL. 1990 Genotype-phenotype correlations in XX males and their bearing on current theories
of sex determination. Hum Genet. 84:198 –202.
7. Kuhnle U, Schwarz HP, Lohrs U, Stengel-Ruthkowski S, Cleve H, Braun A.
1993 Familial true hermaphroditism: paternal and maternal transmission of
true hermaphroditism (46,XX) and XX maleness in the absence of Y- chromosomal sequences. Hum Genet. 92:571–576.
8. Mendonca BB, Barbosa AS, Arnhold IJ, McElreavey K, Fellous M, MoreiraFilho CA. 1994 Gonadal agenesis in XX and XY sisters: evidence for the
involvement of an autosomal gene. Am J Med Genet. 52:39 – 43.
9. Ramos ES, Moreira-Filho CA, Vicente YA, et al. 1996 SRY-negative true
hermaphrodites and an XX male in two generations of the same family. Hum
Genet. 97:596 –598.
10. Teebi AS, Miller S, Ostrer H, et al. 1998 Spastic paraplegia, optic atrophy,
microcephaly with normal intelligence, and XY sex reversal: a new autosomal
recessive syndrome? J Med Genet. 35:759 –762.
11. Bogan JS, Page DC. 1994 Ovary? Testis?–A mammalian dilemma. Cell.
76:603– 607.
12. Goodfellow PN, Lovell-Badge R. 1993 SRY and sex determination in mammals. Annu Rev Genet. 27:71–92.
13. Hawkins JR. 1994 Sex determination. Hum Mol Genet. 3:1463–1467.
14. Hanley NA, Hagan DM, Clement-Jones M, et al. 1999 SRY, SOX9, and DAX1
expression patterns during human sex determination and gonadal development. Mech Dev. In press.
15. Hanley NA, Ball SG, Clement-Jones M, et al. 1999 Expression of steroidogenic
factor 1 and Wilms’ tumour 1 during early human gonadal development and
sex determination. Mech Dev. 87:175–180.
16. Call KM, Glaser T, Ito CY, et al. 1990 Isolation and characterization of a zinc
finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus.
Cell. 60:509 –520.
17. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA. 1990
Homozygous deletion in Wilms tumours of a zinc-finger gene identified by
chromosome jumping. Nature. 343:774 –778.
18. Hastie ND. 1992 Dominant negative mutations in the Wilms tumour (WT1)
gene cause Denys- Drash syndrome–proof that a tumour-suppressor gene
plays a crucial role in normal genitourinary development. Hum Mol Genet.
1:293–295.
19. Barbaux S, Niaudet P, Gubler MC, et al. 1997 Donor splice-site mutations in
WT1 are responsible for Frasier syndrome. Nat Genet. 17:467– 470.
20. Hovmoller ML, Osuna A, Eklof O, et al. 1977 Camptomelic dwarfism. A
genetically determined mesenchymal disorder combined with sex reversal.
Hereditas. 86:51– 62.
21. Tommerup N, Schempp W, Meinecke P, et al. 1993 Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to
17q24.3-q25.1. Nat Genet. 4:170 –174.
22. Foster JW, Dominguez-Steglich MA, Guioli S, et al. 1994 Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.
Nature. 372:525–530.
23. Wirth J, Wagner T, Meyer J, et al. 1996 Translocation breakpoints in three
patients with campomelic dysplasia and autosomal sex reversal map more
than 130 kb from SOX9. Hum Genet. 97:186 –193.
24. Achermann JC, Ito M, Hindmarsh PC, Jameson JL. 1999 A mutation in the
gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet. 22:125–126.
25. Bennett CP, Docherty Z, Robb SA, Ramani P, Hawkins JR, Grant D. 1993
Deletion 9p and sex reversal. J Med Genet. 30:518 –520.
26. Slavotinek A, Schwarz C, Getty JF, Stecko O, Goodman F, Kingston H. 1999
CLINICAL REVIEW
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
Two cases with interstitial deletions of chromosome 2 and sex reversal in one.
Am J Med Genet. 86:75– 81.
Veitia R, Nunes M, Brauner R, et al. 1997 Deletions of distal 9p associated with
46,XY male to female sex reversal: definition of the breakpoints at 9p23.3-p24.1.
Genomics. 41:271–274.
Wilkie AO, Campbell FM, Daubeney P, et al. 1993 Complete and partial XY
sex reversal associated with terminal deletion of 10q: report of 2 cases and
literature review. Am J Med Genet. 46:597– 600.
Bardoni B, Zanaria E, Guioli S, et al. 1994 A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nat Genet. 7:497–501.
Bernstein R, Koo GC, Wachtel SS. 1980 Abnormality of the X chromosome
in human 46,XY female siblings with dysgenetic ovaries. Science. 207:768 –769.
Dabovic B, Zanaria E, Bardoni B, et al. 1995 A family of rapidly evolving genes
from the sex reversal critical region in Xp21. Mamm Genome. 6:571–580.
Ion A, Telvi L, Chaussain JL, et al. 1996 A novel mutation in the putative DNA
helicase XH2 is responsible for male-to-female sex reversal associated with an
atypical form of the ATR- X syndrome. Am J Hum Genet. 58:1185–1191.
Fechner PY, Marcantonio SM, Jaswaney V, et al. 1993 The role of the sexdetermining region Y gene in the etiology of 46,XX maleness. J Clin Endocrinol
Metab. 76:690 – 695.
Toublanc JE, Boucekkine C, Abbas N, et al. 1993 Hormonal and molecular
genetic findings in 46,XX subjects with sexual ambiguity and testicular differentiation. Eur J Pediatr. 152:S70 –S75.
Berkovitz GD, Fechner PY, Marcantonio SM, et al. 1992 The role of the
sex-determining region of the Y chromosome (SRY) in the etiology of 46,XX
true hermaphroditism. Hum Genet. 88:411– 416.
De la Chapelle A, Schroder J, Murros J, Tallovist G. 1977 Two XX males in
one family and additional observations bearing on the etiology of XX males.
Clin Genet. 11:91–106.
Page DC, de la Chapelle A, Weissenbach J. 1985 Chromosome Y-specific DNA
in related human XX males. Nature. 315:224 –226.
Abbas N, McElreavey K, Leconiat M, et al. 1993 Familial case of 46,XX male
and 46,XX true hermaphrodite associated with a paternal-derived SRY-bearing
X chromosome. C R Acad Sci III. 316:375–383.
Manouvrier S, Loeuille GA, Fontaine G, Farriaux JP. 1987 L’hermaphroditisme vrai familial (a propos de deux familles). J Genet Hum. 35:131–144.
Milner WA, Garlick WB, Fink AJ, Stein AA. 1958 True hermaphrodite siblings. J Urol. 79:1003–1009.
Fraccaro M, Tiepolo L, Zuffardi O, et al. 1979 Familial XX true hermaphroditism and the H-Y antigen. Hum Genet. 48:45–52.
Gallegos AJ, Guizar E, Armendares S, et al. 1976 Familial true hermaphorodism in three siblings: plasma hormonal profile and in vitro steroid biosynthesis in gonadal structures. J Clin Endocrinol Metab. 42:653– 660.
Mori Y, Mizutani S. 1968 Familial true hermaphroditeism in genetic females.
Jpn J Urol. 59:857– 864.
Armendares S, Salamanca F, Cantu JM, et al. 1975 Familial true hermaphrodism in three siblings: clinical, cytogenetic, histological and hormonal studies. Humangenetik. 29:99 –109.
Clayton GW, Smith JD, Rosenberg S. 1958 Familial true hermaphroditism in
pre- and postpubertal genetic females. Hormonal and morphologic studies.
J Clin Endocrinol Metab. 18:1349 –1358.
Kasdan R, Nankin HR, Troen P, Wald N, Pan S, Yanaihara T. 1973 Paternal
transmission of maleness in XX human beings. N Engl J Med. 288:539 –545.
Skordis NA, Stetka DG, MacGillivray MH, Greenfield SP. 1987 Familial
46,XX males coexisting with familial 46,XX true hermaphrodites in same pedigree. J Pediatr. 110:244 –248.
Berger R, Abonys D, Nodot A. 1969 Hermaphroditisme vrai et garcon 46,XX
dans une fraternite. Rev Europ Etud Clin Biol. 15:330 –333.
Borges WH, Wald N. 1963 A dimunitive satellited chromosome in a father and
in one of two true hermaphrodite progeny. J Pediatr. 63:474 – 475.
Hawkins JR. 1995 Genetics of XY sex reversal. J Endocrinol. 147:183–187.
Hawkins JR, Taylor A, Goodfellow PN, Migeon CJ, Smith KD, Berkovitz
GD. 1992 Evidence for increased prevalence of SRY mutations in XY females
with complete rather than partial gonadal dysgenesis. Am J Hum Genet.
51:979 –984.
Jager RJ, Harley VR, Pfeiffer RA, Goodfellow PN, Scherer G. 1992 A familial
mutation in the testis-determining gene SRY shared by both sexes. Hum Genet.
90:350 –355.
Vilain E, McElreavey K, Jaubert F, Raymond JP, Richaud F, Fellous M. 1992
Familial case with sequence variant in the testis-determining region associated
with two sex phenotypes. Am J Hum Genet. 50:1008 –1011.
Nasrin N, Buggs C, Kong XF, Carnazza J, Goebl M, Alexander-Bridges M.
1991 DNA-binding properties of the product of the testis-determining gene
and a related protein. Nature. 354:317–320.
493
55. Harley VR, Jackson DI, Hextall PJ, et al. 1992 DNA binding activity of
recombinant SRY from normal males and XY females. Science. 255:453– 456.
56. Eicher EM, Washburn LL. 1986 Genetic control of primary sex determination
in mice. Annu Rev Genet. 20:327–360.
57. Schmitt-Ney M, Thiele H, Kaltwasser P, Bardoni B, Cisternino M, Scherer
G. 1995 Two novel SRY missense mutations reducing DNA binding identified
in XY females and their mosaic fathers. Am J Hum Genet. 56:862– 869.
58. Hines RS, Tho SP, Zhang YY, et al. 1997 Paternal somatic and germ-line
mosaicism for a sex-determining region on Y (SRY) missense mutation leading
to recurrent 46,XY sex reversal. Fertil Steril. 67:675– 679.
59. Bilbao JR, Loridan L, Castano L. 1996 A novel postzygotic nonsense mutation
in SRY in familial XY gonadal dysgenesis. Hum Genet. 97:537–539.
60. Barbosa AS, Ferraz-Costa TE, Semer M, Liberman B, Moreira-Filho CA. 1995
XY gonadal dysgenesis and gonadoblastoma: a study in two sisters with a
cryptic deletion of the Y chromosome involving the SRY gene. Hum Genet.
95:63– 66.
61. Sternberg WH, Barklay DL, Kloepfer W. 1968 Familial XY gonadal dysgenesis. N Engl J Med. 278:695–700.
62. Espiner EA, Veale AM, Sands VE, Fitzgerald PH. 1970 Familial syndrome of
streak gonads and normal male karyotype in five phenotypic females. N Engl
J Med. 283:6 –11.
63. Boczkowski K. 1976 Familial occurrence of gonadal tumors in XY females with
breast development. Hum Genet. 33:289 –294.
64. German J, Simpson JL, Chaganti RS, Summitt RL, Reid LB, Merkatz IR. 1978
Genetically determined sex-reversal in 46,XY humans. Science. 202:53–56.
65. Mann JR, Corkery JJ, Fisher HJ, et al. 1983 The X linked recessive form of XY
gonadal dysgenesis with a high incidence of gonadal germ cell tumours:
clinical and genetic studies. J Med Genet. 20:264 –270.
66. Berg FD, Kurzl R, Hinrichsen MJ, Zander J. 1989 Familial 46,XY pure gonadal
dysgenesis and gonadoblastoma/dysgerminoma: case report. Gynecol Oncol.
32:261–267.
67. Nivelon A, Nivelon JL, Mabille JP, et al. 1992 New autosomal recessive
chondrodysplasia–pseudohermaphrodism syndrome. Clin Dysmorphol.
1:221–227.
68. Cameron FJ, Hageman RM, Cooke-Yarborough C, et al. 1996 A novel germ
line mutation in SOX9 causes familial campomelic dysplasia and sex reversal.
Hum Mol Genet. 5:1625–1630.
69. Acquafredda A, Vassal J, Job JC. 1987 Rudimentary testes syndrome revisited.
Pediatrics. 80:209 –214.
70. Mueller RF. 1994 The Denys-Drash syndrome. J Med Genet. 31:471– 477.
71. Veitia RA, Nunes M, Quintana-Murci L, et al. 1998 Swyer syndrome and
46,XY partial gonadal dysgenesis associated with 9p deletions in the absence
of monosomy-9p syndrome. Am J Hum Genet. 63:901–905.
72. Domenice S, Yumie Nishi M, Correia Billerbeck AE, et al. 1998 A novel
missense mutation (S18N) in the 5⬘ non-HMG box region of the SRY gene in
a patient with partial gonadal dysgenesis and his normal male relatives. Hum
Genet. 102:213–215.
73. McElreavey KD, Vilain E, Boucekkine C, et al. 1992 XY sex reversal associated
with a nonsense mutation in SRY. Genomics. 13:838 – 840.
74. Josso N, Briard ML. 1980 Embryonic testicular regression syndrome: variable
phenotypic expression in siblings. J Pediatr. 97:200 –204.
75. Kennerknecht I, von Saurma P, Brenner R, et al. 1995 Agonadism in two
sisters with XY gonosomal constitution, mental retardation, short stature,
severely retarded bone age, and multiple extragenital malformations: a new
autosomal recessive syndrome. Am J Med Genet. 59:62– 67.
76. Naffah J. 1989 Syndrome de regression testiculaire familial. Bull Acad Natl
Med. 173:709 –714.
77. Verloes A, Gillerot Y, Delfortrie J, et al. 1990 Male pseudohermaphroditism
with persistent mullerian structures, mental retardation and Borjeson-Forssman-Lehmann-like features: a new syndrome? Genet Couns. 1:219 –225.
78. Fuqua JS, Sher ES, Fechner PY, et al. 1996 Linkage analysis of a kindred with
inherited 46,XY partial gonadal dysgenesis. J Clin Endocrinol Metab.
81:4479 – 4483.
79. Phansey SA, Satterfield R, Jorgenson RJ, et al. 1980 XY gonadal dysgenesis
in three siblings. Am J Obstet Gynecol. 138:133–138.
80. Barr ML, Carr DH, Plunkett ER, Soltan HC, Wiens RG. 1967 Male pseudohermaphroditism and pure gonadal dysgenesis in sisters. Am J Obstet Gynecol.
99:1047–1055.
81. Kingsbury AC, Frost F, Cookson WO. 1987 Dysgerminoma, gonadoblastoma,
and testicular germ cell neoplasia in phenotypically female and male siblings
with 46 XY genotype. Cancer. 59:288 –291.