Download Multiple Congenital Genitourinary Anomalies in a

Multiple Congenital Genitourinary Anomalies in a
Polled Goat
WILLIAM W. KING, DVM, PHD, DIPLOMATE, ACLAM,1,2* MELVIN E. YOUNG,1 AND M. EUGENE FOX, DVM3
A 1-day-old, Toggenburg/Nubian crossbred goat of polled parentage was referred for necropsy because of a large (diameter, 5
cm) bladder-like mass protruding from the perineal midline and difficult urination. Differential diagnoses included cutaneous
cyst, ectopic urinary bladder, and urethral diverticulum/dilatation. Several genitourinary aberrations were noted. A second, smaller
(diameter, 1 cm), more distal cystic structure was adjacent to an ambiguous prepuce. Testicles were discovered within a constricted, subcutaneous space near the inguinal canals. A rudimentary penis was located dorsal to the penile urethra with no appreciable
urethral process. A tiny external urethral orifice was discerned only after liquid was injected into the lumen of the cystic structures,
confirming their identity as urethral dilatations. The dilatations were separated by a constricting band of fibrous tissue. No other
significant findings were detected. This case illustrates a combination of congenital anomalies including bilateral cryptorchidism
with scrotal absence, segmental urethral hypoplasia, and urethral dilatation, most likely associated with the intersex condition seen
in polled breeds. The continued production and use of small ruminants as animal models demands the prompt recognition of
congenital anomalies. This case also exemplifies the precautions required when breeding goats with polled ancestry.
The domestic goat (Capra hircus) has historically served and
continues to play an important role in biomedical research (1).
Many small breeds are available, facilitating common laboratory animal husbandry practices. Because of their large, easily
accessed jugular veins, goats frequently are used in the production of antiserum. Along with sheep (Ovis aries), these small
ruminants are common subjects in reproductive studies. Because of their natural affinity for caprine arthritis-encephalitis
virus, goats also are used to investigate the pathogenesis of
lentivirus infection. This species has been specifically recommended as a spontaneous animal model for the following
human diseases: congenital hypothyroidism (2), neuritic
plaques (secondary to scrapie; 3), pulmonary adenomatosis
(jaagziekte, or alveolar cell carcinoma; 4), amelia, or congenital absence of limbs (5), and glomerulonephritis (6).
Many conditions are known to be inherited in various goat
breeds, including afibrinogenemia (Saanen), beta-mannosidosis
(Nubian), bipartite scrotum (Angora), brachygnatha or abnormally shortened mandible, cryptorchidism (Angora), excessive
facial hair (Angora), gynecomastia or excessive development of
male mammary glands, hereditary goiter (Dutch), inherited
abortion (South African Angora), the spasm-inducing disorder
myotonia congenita, recessive atrichosis or hairlessness,
Robertsonian translocation, short tendons (Australian Angora),
sperm granulomas, supernumerary teats, and testicular hypoplasia (7). Although numerous congenital disorders have been
reported in goats, the presence of multiple anomalies in a single
case is rather rare (8). This case report describes a combination
of abnormalities most likely associated with the intersex condition in a polled kid.
Case History
A 1-day-old goat was referred for necropsy because of dysuria
and a large bladder-like mass extending from the ventral perineal
midline. The animal was examined by the referring veterinarian; euthanasia was elected and performed on-site. The kid was
one of a pair of twins from a polled Toggenburg dam and polled
1
Research Service (151), Department of Veterans Affairs, Edward Hines Jr. VA Hospital,
Hines, Illinois 60141; 2Department of Pathology, Loyola University Medical Center, Maywood,
Illinois 60153; 3House-Call Veterinary Service, Lockport, Illinois 60441
*
Corresponding author: William W. King, DVM, PhD, Diplomate, ACLAM, Office of
Research Services, School of Medicine, University of Louisville, Louisville, Kentucky 40292
Volume 41, No. 5 / September 2002
Nubian/Toggenburg sire. The owner reported that the doe had
completed a normal gestation period on a diet of natural grass/
alfalfa hay and water. The surviving twin appeared to be a normal male.
Upon initial gross examination, the kid appeared in good
nutritional status. The prepuce demonstrated shared characteristics of female and male, with the preputial opening located
intermediately between that expected of a male or female. The
prepuce was characterized as a small (approximately 1 cm)
opening in the ventral abdominal skin, exposing a slightly
globoid, reddened mucous membrane with little recognizable
structure. A small (approximately 0.2 × 1.0 cm) cartilaginous
structure was palpable dorsal to the prepuce. No urethral process was present in the prepuce, and no other external genitalia
were identifiable.
A 5-cm, vascularized, bladder-like mass extended from the
ventral perineal midline (Fig. 1). A similar, smaller (approximately 1 cm) structure was located adjacent to the prepuce. The
two were separated by a constricting band of fibrous tissue just
proximal to the area of the preputial urethra. The surface of
these thin-walled structures was smooth with no evidence of hair
or other skin adnexa. A tiny external urethral orifice was recognized only after liquid was injected into, and expressed from,
the bladder-like mass. Dissection revealed that the lumen of these
structures was confluent with the pelvic urethra.
Upon further examination, testicles were discovered within a
short inguinal canal confined within the subcutis (Fig. 2). Grossly,
the testes appeared normal, although the ductus deferens appeared distended throughout the length of the colliculus
seminalis to the epididymis. No indication of a scrotum was evident. No rudimentary ovarian or uterine structures were located,
and no other lesions were appreciated grossly.
Differential diagnoses for the larger bladder-like structure
included cutaneous cyst, ectopic urinary bladder, and urethral
dilatation or diverticulum. Dissection of the perineum confirmed
that both structures constituted dilatations/diverticula of the
perineal urethra. Further exploration identified the urethral
lumen from the urinary bladder to the small external urethral
orifice (Fig. 3). Gross observations were consistent with the diagnoses of bilateral cryptorchidism, segmental urethral
hypoplasia, and urethral diverticula.
The preputial ambiguity strongly suggested a genetic condition involving reproductive development. In neonatal ruminants,
CONTEMPORARY TOPICS © 2002 by the American Association for Laboratory Animal Science
39
Figure 3. Dissected genitourinary tract of affected goat. A catheter has
been inserted through the urethra into the urinary bladder. A, external
urethral orifice; B, large urethral diverticulum; C, seminal colliculus; D,
small urethral diverticulum.
Discussion
Figure 1. External appearance of anomalies. Note the two ventral midline cyst-like masses and the ambiguous prepuce.
Figure 2. Location of cryptorchid testicle (A) in subcutaneous inguinal
canal (B, vaginal ring).
the distal aspect of the penis, including the urethral process in
goats, is adhered to the prepuce (9). However, the testicles normally are descended at birth into a well-developed scrotum (7).
In this case, only a rudimentary penile structure was identifiable, the prepuce was located in an intermediate position, and,
unlike in the surviving twin male, no scrotum was evident. In
light of these findings, the known parentage, and the similarities with other clinical reports, the presumptive etiology for the
anomalies seen in this case is the intersex condition seen in polled
breeds. Limitations in the tissues available for additional diagnostic evaluation made definitive differentiation from
freemartinism impossible.
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CONTEMPORARY TOPICS © 2002 by the American Association for Laboratory Animal Science
Congenital abnormalities. Developmental anomalies may result from both genotypic and environmental influences, or a
combination of both, with an interruption of the “temporal-spatial requirements of development” (10). Congenital or hereditary
abnormalities of the urethra occur infrequently in all animal
species and include malformations of the urethral wall and orifice (e.g. hypospadias, epispadias with exstrophy or eversion of
the bladder), urethral aplasia and agenesis, ectopic urethra, urethral duplication, and urethrorectal or urethrovaginal fistula (11,
12). In goats, inherited anomalies associated with the distal urinary tract and/or reproductive tract include bipartite scrotum
and cryptorchidism in Angora goats, testicular hypoplasia, sperm
granulomas, and intersex (7).
Reports of urethral diverticula in neonatal goats are uncommon. In one description, a 2-day-old goat of unspecified breed
presented for urinary obstruction with a urethral diverticulum
(confirmed via positive contrast urethrography), bipartite scrota,
and preputial hypoplasia with an imperforate urethral process
(8). Although no etiology was determined, surgical correction
(urethrostomy, obliteration of the diverticula, and castration)
was effective. In a report of 11 goats between 2-6 months of age
that presented with continuous dribbling of urine, congenital
urethral diverticula were discovered and successfully treated by
surgical resection. Ten of the kids, which were of unstated breed,
also had scrotal anomalies, including bipartite scrotum and
monorchidism (13).
Although the term “pseudohermaphrodite” has been used to
describe animals retaining the gonads of one gender with sex
characteristics of the other, such as genotype or reproductive
morphology (14), the preferred term for gender inconsistencies in goats is “intersex” (7). This condition results from sex
chromosomal abnormalities and has been defined as “ambiguity in the structure of the gonads, reproductive tract, or external
genitals” (14). The disorder is strongly associated with the polled
condition in goat breeds of western European descent (Saanen,
Alpine, and Toggenburg) and is less commonly found with
freemartinism (15, 16).
There have been several descriptive surveys of the intersex
condition in dairy goats. Hamerton and colleagues examined
35 cases of polled intersexuality and found that the vast majority
(97%) of cases were genetically female (60,XX) with mixed male
phenotype and that there was a low percentage (3%) of
freemartins (60,XX/60,XY) (15). In 1943, Eaton described 29
cases of “pseudohermaphroditism,” classifying each into four
“female-predominant” and four “male-predominant” categories
Volume 41, No. 5 / September 2002
based on external anatomy, with six additional categories based
on internal anatomy (17). The case we describe shared many
characteristics of the class 2 male-predominant type, with the
exception of the urethral opening at the tip of the genitalia
and urethral diverticula at the expanse of the perineal raphe
(central midline). Also of interest, Eaton noted that 29% of
the male-predominant cases presented with hypospadias, or
ventral opening of the penile urethra. The occurrence of the
urethral diverticula in this case may represent an anomalous
closure of the ventral urethral wall, similar to hypospadias, or
be associated with agenesis/hypoplasia of the urethral opening. Other findings reported to occur in conjunction with the
intersex condition include cryptorchidism, in which the testes
typically are retained within the abdomen but may be partially
or fully descended (16).
A more recent report involving an 18-day-old intersex FrenchAlpine/Nubian goat had remarkable similarities to the case
described in the present report (18). This kid presented with a
ventral midline urethral dilatation associated with a hypoplastic
distal urethra at the prepuce. The urethra was found to be distinctly separate from a rudimentary penis; surgical correction
and urethrostomy was performed. During an exploratory abdominal surgery for gonadectomy, testicles were located adjacent to
each kidney. Blood karyotype analysis revealed that the goat was
genotypically female (60,XX).
Genetic anomalies. Gender development results from complex interactions of sex- and autosomal-linked genes. The SRY
(sex-determining region Y) gene directs mammalian embryos
to develop testes, which subsequently support the male phenotype by producing Mullerian inhibiting proteins and testosterone
(19, 20). This cascade of genetic events is not simple, however,
as is illustrated in the intersex condition seen in polled goats.
The interaction between hornlessness and intersex in genetically female (XX) goats, first suggested by Asdell in 1944 (21),
has been dubbed the Polled Intersex Syndrome (PIS) and is
thought to be caused by an interference with the development
of female characteristics by aberrant expression of male-promoting gene products (7).
Phenotypically, the mutation (P), which is either a single
pleiotropic gene or two intimately linked genes, expresses
polledness in an autosomal dominant fashion and results in
sex-reversal in females as an autosomal recessive trait (22). The
mutation partially simulates the Y chromosome, encouraging
the development of testicular tissue by generating H-Y antigen
(16, 23, 24). Interestingly, the PIS XX intersex is SRY-negative,
a fact that supports theories of autosomal gene involvement in
male gender development independent the Y-chromosome or
of X-Y or autosomal-Y translocation of SRY genes (25, 26). The
mutation causing PIS recently has been identified as an 11.7kb deletion on chromosome 1 (20, 27, 28). Females that are
homozygous for the polled gene (PP) will become infertile intersex (7); fertile polled females therefore must be heterozygous
for the polled gene (Pp) (16).
Intersex secondary to freemartinism is another possibility in
the described case. The pathogenesis of this condition involves
the sharing of cells and hormones between a male and female
fetus following placental fusion and anastomosis, resulting in
chimerism in the female twin (16). Karyotype analysis generally is used to differentiate polled intersex (genetically female,
XX) from freemartinism (chromosomal chimerism, XX/XY).
This assay can be performed on lymphocytes from whole blood
or cultured renal or pericardial fibroblasts (10). Several authors
have described the use of polymerase chain reaction (PCR) techniques for determining sex in goats (29, 30). Examination of
fresh tissue with either PCR-based assays or Southern blot for
the presence of the Y-chromosome-associated Zfy and Sry regions can differentiate polled intersex from freemartin
Volume 41, No. 5 / September 2002
Figure 4. Breeding schemes associated with the intersex condition. Note
that a homozygous polled doe (PP) is infertile and therefore not shown.
(Modified from Smith and Sherman, 1994.)
chimerism (25, 26). Unfortunately, appropriate tissues were not
archived from the described goat to perform these confirmatory steps. However, the prevalence of placental fusion is much
lower in goats than in cattle, making freemartinism much less
common in goats (7).
Reproductive management. Institutions and animal breeders
producing goats may find the congenital lack of horns a desirable characteristic with practical and humane advantages over
surgical dehorning or disbudding. However, there are several
problems associated with the polled condition. An understanding of the mechanisms of transmission of PIS therefore is
extremely important when designing a production program.
Figure 4 illustrates the breeding crosses that may result in intersex offspring.
The intersex condition in European goats can be avoided by
ensuring that one parent was born with horns (genotypically
horned), that is, homozygous recessive for the polled gene (p).
This precaution will prevent any female offspring from expressing the intersex associated with the homozygous dominant polled
gene (P) (7). Note that a central whorl of hair on the dorsal
cranium is present in polled goats; two whorls overlying the area
of horn growth is present in disbudded kids (7).
In programs designed to increase the number of polled offspring, the goals of increasing fertility and decreasing the
potential for intersexes often conflict. To maximize reproductive output, breeding horned bucks (pp) to fertile (therefore
heterozygous, Pp) polled does, which often produce more offspring including twins and triplets (16), will result in only 50%
of the offspring being polled but with no possibility of PIS females. Although there are disadvantages in using homozygous
polled bucks (PP), which frequently develop sperm granulomas
resulting in obstruction of the head of the epididymis and testicular hypoplasia (7, 16), the cross of such a sire with a
genotypically horned doe (pp) results in 100% heterozygous
polled offspring, also with no potential for producing polledassociated intersexes. Crossing a polled buck (regardless of
genotype) with a doe born horned (pp) will result in a 6/8
(75.0%) probability of polled offspring with no possibility of PIS
females. Breeding a polled buck (again, regardless of genotype)
with a polled doe (Pp) will result in a 7/8 (87.5%) probability of
polled offspring but a concurrent 3/8 (37.5%) chance of intersex in female kids.
Alternatively, breeding schemes can be designed to specifically produce PIS animals for use as models of the human
XX-male intersex condition. In humans, conditions leading to
intersex may occur at any time during intrauterine development
and may lead to a spectrum of consequences ranging from overt
anatomical and physiological anomalies to more elusive abnormalities not appreciated until sexual maturity (31). Although
considerable work has focused on the appropriate timing of treatment, intersexuality continues to result in a significant incidence
in gender identity disorders (32). The presentation of such infants produces a two-fold crisis: 1) challenging medical and
CONTEMPORARY TOPICS © 2002 by the American Association for Laboratory Animal Science
41
surgical interventions, and 2) extensive sociological and psychological adjustment (33, 34). Of particular interest, it has been
recently suggested that the PIS gene is homologous to the locus
linked to blepharophimosis ptosis epicanthus inversus syndrome
(BPES), a condition associated with ovarian dysfunction and
epidermal thickening of the eyelid in affected humans (27, 35).
Intentional production of intersex goats is relatively straightforward—the cross of a fertile polled female goat (Pp) with a
homozygous polled male (PP) will result in a 50% chance of PIS
in female offspring. Thus, the polled goat will continue to advance the knowledge of mammalian XX-male sex reversal and
other intersex conditions as well as the underlying intricate interactions involved in gender development.
This report describes an interesting combination of congenital anomalies in a polled goat kid, including bilateral inguinal
cryptorchidism and scrotal aplasia, segmental urethral hypoplasia, and urethral diverticula. These lesions most likely were
associated with the intersex syndrome recognized in various
polled European breeds. Expression of gene-associated disorders will continue to become more prevalent should breeding
programs for goats become more intense. Proper design of breeding programs can minimize or maximize the probability of
producing intersex animals.
Acknowledgments
This material is based upon work supported by the Office of Research
and Development of the Department of Veterans Affairs. An abstract of
this report was presented at the 1998 National Meeting of the American
Association for Laboratory Animal Science in Cincinnati, Ohio.
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