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Inherited Disorders in Sexual Development
V. N. Meyers-Wallen
Normal Sexual Development
From the James A. Baker Institute for Animal Health,
Cornell University, College of Veterinary Medicine, Ithaca, NY 14853. This paper was delivered at the International Workshop on Canine Genetics at the College
of Veterinary Medicine, Cornell University, Ithaca, New
York, July 12–13, 1997.
q 1999 The American Genetic Association 90:93–95
Normal mammalian sexual development
depends on the successful completion of
a series of steps that are under genetic
control. For simplicity, this series is described in three key steps: establishment
of chromosomal sex, gonadal sex, and
phenotypic sex.
Chromosomal sex is normally determined at fertilization. The zygote has either an XX or an XY chromosome constitution that is maintained by mitosis in all
cell types as the embryo develops. The
early embryo is sexually indifferent in that
the genital morphology is similar and the
gonads are undifferentiated in XX and XY
embryos.
Gonadal sex is determined by genetic
sex, which normally corresponds to chromosomal sex. A testis-determining gene
on the Y chromosome, Sry, encodes a protein that initiates testis differentiation
( Koopman et al. 1991). Sox9, an autosomal
gene, is involved in the testis differentiation pathway. Two normal Sox9 alleles are
necessary for testis development in XY
males having Sry ( Foster et al. 1994). Sox9
expression in embryonic gonads is consistent with a role in Sertoli cell differentiation (Morais da Silva et al. 1996). Normal
XX individuals, lacking the Sry gene, do
not develop testes. The gonadal expression pattern of the X-linked Dax1 gene
( Bardoni et al. 1994) is consistent with a
role in ovarian differentiation, although it
also has a role in adrenal, hypothalamic,
and pituitary development (Swain et al.
1996). Of interest, other genes that are important in development of the indifferent
gonads are also necessary for renal (WT1;
Bruening et al. 1992) and adrenal development (SF1; Luo et al. 1994). Thus the
study of abnormal gonadal differentiation
is revealing developmental gene pathways
that are shared by different organ systems.
Phenotypic sex is determined by the
presence or absence of a testis, since gonadectomy of XX or XY embryos prior to
gonadal differentiation results in development of a female phenotype (Jost et al.
1973). This led to the conclusions that
ovarian hormones are not necessary for
female embryonic differentiation, and the
default phenotypic plan is female. Phenotypic masculinization depends on the
presence of a testis and its hormonal secretions, which divert the phenotypic plan
from female to male. Sertoli cells secrete
Mullerian inhibiting substance (MIS), also
known as anti-Mullerian hormone (Amh),
which causes regression of the Mullerian
duct system. Leydig cells secrete testosterone which promotes Wolffian duct differentiation (epididymis and vas deferens). In other target organs, testosterone
is converted to dihydrotestosterone
( DHT ) by the enzyme 5-alpha reductase.
The prostate and external genitalia develop in response to DHT. The action of both
androgens is mediated through binding to
the intranuclear androgen receptor. Male
external genitalia are completed by descent of the testes. However, the control
of testicular descent is incompletely understood and may differ between species.
Inherited Disorders of Sexual
Development
In this article, defects are classified according to the first step at which development differs from normal as errors in
chromosomal sex, gonadal sex, or phenotypic sex ( Table 1).
Abnormalities of Chromosomal Sex
The primary defect in these animals is an
abnormality in the number or structure of
the sex chromosomes, such as monosomy
or trisomy. In general, these defects occur
through random errors in meiosis or mitosis and may not be transmitted further
93
Table 1. Main features of selected disorders of sexual development a
Gonad
Mullerian
duct
Wolffian duct
derivatives derivatives
External genitalia
Diagnosis
XXY
Testis
None
Male
XXY syndrome
XO
Streak gonad
Epididymis
Vas deferens
None
Female
XO syndrome
Varies
Female/ambiguous/male Chimera
Abnormality of
Karyotype
Chromosomal sex
Gonadal sex
XX/XY
Uterus
Oviduct
Vagina
Ovary/ovotestis/testis Varies
XX
Testis/Ovotestis
Uterus
6 Epididymis and
6 oviduct
vas deferens
Ovary
Uterus
Oviduct
Uterus
Oviduct
None
Phenotypic sex
Female pseudohermaphrodite XX
Male pseudohermaphrodite
a
XY
Testis
XY
Testis
Male/ambiguous/female
XX sex reversal
XX male or
XX true hermaphrodite
6 Epididymis
Ambiguous or male
Exogenous androgen/progestagen
Epididymis
Vas deferens
None/6 epididymis and
vas deferens
Male
6 cryptorchid
Female/ambiguous
Persistent Mullerian duct syndrome
Complete or incomplete Tfm
Examples are disorders reported in dogs or cats.
than the single affected animal in the pedigree. The XXY syndrome ( Klinefelter’s
syndrome in humans) has been reported
in several mammals. It is most often recognized in male cats that have a calico or
tortoise-shell coat. Similarly, animals with
XO and XXX chromosome constitutions,
and chimeras and mosaics have also been
described (reviewed in Meyers-Wallen
1993).
Abnormalities of Gonadal Sex
In these disorders, the chromosomal and
gonadal sex of the individual do not agree.
Affected individuals are termed sex reversed. Animals with XY sex reversal fail
to develop testes, and may have hypoplastic ovaries or streak gonads. Since a
functional testis is absent, a female phenotype results, and these individuals are
termed XY females. For example, XY sexreversed horses are usually presented as
mares that fail to cycle and are sterile.
This is likely to be an inherited defect, but
the etiologic mutation is unknown. Some
human XY females have SRY mutations,
but others have a normal SRY. There are
at least two autosomal loci that have been
linked to human XY sex reversal (Goodfellow and Lovell-Badge 1993).
Individuals with XX sex reversal have a
normal female karyotype but develop
varying amounts of testicular tissue.
When both gonads are composed entirely
of testis, they are termed XX males. More
commonly, the gonads contain both ovarian and testicular tissue, and these are XX
true hermaphrodites. It has been demonstrated that translocation of the SRY gene
from the Y to the X chromosome is responsible for most human XX males. How-
94 The Journal of Heredity 1999:90(1)
ever, 20% of human XX males have neither
the SRY gene nor any other Y chromosome sequence (Goodfellow and LovellBadge 1993). Sry-negative XX sex reversal
syndromes in goats ( Hamerton et al.
1969), pigs (Sittman et al. 1980), and purebred dogs (Meyers-Wallen and Patterson
1988; Meyers-Wallen et al. 1995a,b) are inherited as simple autosomal recessive
traits. Isolated cases of XX sex reversal
have been reported in the Pasa Fino horse
(Meyers-Wallen et al. 1997) and the llama
( Lopez et al. 1998; Wilker et al. 1994).
Abnormalities of Phenotypic Sex
In disorders of this category, chromosomal and gonadal sex agree, but the internal
or external genitalia are ambiguous to
some degree. Affected individuals are either male or female pseudohermaphrodites.
Female pseudohermaphrodites are XX
and have ovaries, but also exhibit androgen-dependent masculinization of the genitalia. There is frequently a history of androgen or progestagen administration to
the dam during gestation of the affected
animal (reviewed in Meyers-Wallen 1993).
Adrenogenital syndromes, a well-characterized cause of female pseudohermaphroditism in humans, has not been described to our knowledge in domestic animals. These are inherited defects in the
steroid enzyme pathway that impair cortisol production.
Male pseudohermaphrodites are XY,
have bilateral testes, and have genitalia
that are female to some degree. Two etiologically distinct categories are recognized: failure of Mullerian duct regression
and failure of androgen-dependent masculinization.
Failure of Mullerian duct regression.
Persistent Mullerian duct syndrome
(PMDS), in which the Mullerian ducts fail
to regress, has been reported in the miniature schnauzer, basset hound, and the
cat (reviewed in Meyers-Wallen 1993). Affected miniature schnauzers have oviducts, uterine horns, uterine body, cervix,
and cranial vagina, as well as male internal
and external genitalia. Approximately 50%
are cryptorchid. In this breed, PMDS is inherited as a simple autosomal recessive
trait with expression limited to XY males.
Affected embryos produce MIS throughout the critical period for Mullerian duct
regression (Meyers-Wallen et al. 1993),
which is supportive of a receptor defect.
Failure of androgen-dependent masculinization. The phenotype in these disorders can vary from severe (complete
failure) to mild (incomplete failure). Affected individuals are XY and have bilateral testes. The Mullerian ducts regress
normally, but structures dependent upon
androgens for masculinization fail to develop, or develop incompletely. In humans, there are a number of different defects that produce a similar phenotype,
which are of three broad categories.
The first group includes defects in the
hypothalamic-pituitary-testis axis, such as
abnormal gonadotropin secretion or abnormal steroid synthesis, which result in
insufficient testosterone secretion. Hypospadias, an abnormality in the location of
the urinary orifice, may be an example in
dogs. This defect results from incomplete
masculinization of the urogenital sinus in
formation of the male urethra. It has been
reported as a familial defect in purebred
dogs such as the Boston terrier ( Hayes
and Wilson 1986). Teratogen-induced hypospadias has been reported in other species. Although hypospadias may be initiated by many factors, the common pathophysiology may be inadequate embryonic or fetal androgen production.
The second group of defects caused by
a failure of androgen-dependent masculinization in humans is characterized by 5alpha reductase deficiency. The resultant
DHT deficiency produces incomplete masculinization of the urogenital sinus, genital
tubercle, and genital swellings. Testosterone-dependent structures masculinize
normally. This has not been reported to
our knowledge in domestic animals.
The third group of human defects is due
to target organ insensitivity to androgens
(androgen resistance or testicular feminization [Tfm] syndromes). These are
caused by quantitative or qualitative defects in the androgen receptor and are Xlinked inherited disorders in mammals. Affected individuals are XY and have bilateral testes and normal Mullerian duct regression. In animals having a nonfunctional androgen receptor, Wolffian duct derivatives are absent, and the external
genitalia are female, as described in the
cat and the horse. These are examples of
the complete form of androgen resistance.
The phenotypic spectrum in humans ranges from the incomplete to complete forms.
Affected humans can be normal but infertile males, individuals with ambiguous
genitalia, or phenotypic females with complete androgen resistance.
Miscellaneous male pseudohermaphroditism. Cryptorchidism is included here
because the mechanism of abnormal tes-
tis descent is incompletely understood.
While cryptorchidism can be associated
with other defects in sexual development,
it also occurs as an isolated defect. As an
isolated defect, cryptorchidism is the
most common disorder of sexual development in dogs, occurring in as many as
13% of dogs presented to small animal
clinics ( Dunn et al. 1968). It is likely that
some forms of canine cryptorchidism are
inherited, since there is a high frequency
in some breeds and within some families
of breeds, and the frequency increases
with inbreeding. In Angora goats, it has
been proposed that cryptorchidism is inherited as a single locus, sex-limited, autosomal recessive trait. In swine, it has
been reported as a sex-limited autosomal
trait involving at least two gene loci.
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Corresponding Editor: Gregory M. Acland
Meyers-Wallen • Inherited Disorders in Sexual Development 95