Persistent Mullerian Duct Syndrome in a Miniature Schnauzer Dog with Signs of Feminization and a Sertoli Cell Tumour

A 5‐year‐old male Miniature Schnauzer was presented with unilateral cryptorchidism and signs of feminization. Abdominal ultrasonography revealed an enlarged right testis and a large, fluid‐filled cavity that appeared to arise from the prostate. Computed tomography revealed the cavity to be consistent with an enlarged uterine body, arising from the prostate, and showed two structures resembling uterine horns that terminated close to the adjacent testes. The dog had a normal male karyotype, 78 XY. Gonadohysterectomy was performed and both the surgical and the histological findings confirmed the presence of a uterus in this male animal, resulting in a diagnosis of persistent Mullerian duct syndrome (PMDS). The enlarged intra‐abdominal testis contained a Sertoli cell tumour. Computed tomography proved to be an excellent diagnostic tool for PMDS.     

Intersexuality in dogs: causes and genetics

Failures in the establishment of chromosomal, gonadal and phenotypic sex can cause intersexuality in dogs. Thus, diagnosis of chimaerism, mosaicism, sex reversal syndrome, and male or female pseudohermaphroditism in intersex individuals has to be based on the inspection of the chromosomes, gonads and the phenotypic appearance of the reproductive organs. In a study over two years, seven dogs of different breeds suspected to be intersexes were cytogenetically investigated. A sry-negative XX-sex reversal syndrome was diagnosed in a Jack Russel Terrier. In a mixbred dog a persistent Mullerian duct syndrome (PMDS) was found and a Border Terrier Dog showed an XX/XY chromosomal chimaerism. In further four dogs of different breeds, a female constitution of sex chromosomes was seen. As a sign of intersexuality each of these dog showed an enlarged clitoris. A differentiation between XX-sex reversal syndrome and female pseudohermaphroditism was not possible because there was no information on the internal genital tract and gonads available.     

Laparoscopic gonadectomy in dogs with ovotesticular disorder of sexual development

Disorders of sexual development (DSD) in dogs involve most commonly an XX sex reversal syndrome, treated conventionally by gonadohysterectomy. The objective of the present case series is to describe the surgical treatment and long-term follow-up of dogs undergoing laparoscopic gonadectomy without hysterectomy for treatment of ovotesticular DSD. Six female dogs clinically diagnosed with DSD were retrospectively included in the study when laparoscopic gonadectomy was performed and histology confirmed the presence of abnormal gonads. The dogs were evaluated by ultrasound after 6 months, and owners were contacted by phone for the long-term reevaluation. Laparoscopic gonadectomy was performed using 2- or 3-portal midline techniques with 3- and/or 5-mm instruments. Additional procedures were performed in 5 dogs, including os clitoris removal in 4 dogs and vulvoplasty in 1 dog. Histological analysis of the gonads reported 11 ovotestes and 1 testis. No major or minor complications occurred perioperatively. Ultrasonographic reevaluation was performed in 5/6 dogs and the remaining abdominal genital system was considered normal. Median long-term follow-up was 617 days (range, 265–1597) with none of the dogs having any symptom related to DSD. Therefore, laparoscopic gonadectomy is a valid alternative for dogs with ovotesticular DSD and is less invasive than conventional open techniques. Removal of the gonads avoids future development of hormone-related diseases of the remaining genital tract.     

Testicular feminization syndrome in a mare.

Testicular feminization syndrome was diagnosed in a mare with aggressive, stallion like behavior and a history of infertility. She was found to have a high baseline testosterone concentration suggesting that testicular tissue was present, and ovarian-like structures examined by use of transrectal ultrasonography had the appearance typical of testicular tissue. Although her external female genitalia appeared normal, her vagina ended in a blind sac, and no cervix or uterus were identified. Surgery was performed, and structures removed from the abdominal cavity were determined to be hypoplastic testicles. Removal of the testicular tissue resulted in complete resolution of her aggressive behavior. Chromosomal evaluation revealed that the mare had 64X,Y (normal male) karyotype. Testicular feminization syndrome is a condition characterized by insensitivity of reproductive tissues to androgens during development because of an abnormality in androgen receptors. This androgen insensitivity results in development of normal external female genitalia, with high testosterone concentrations being released from developing testicles. Testicular feminization syndrome has not been commonly diagnosed in horses, but should be considered as a differential diagnosis for overly aggressive mares with a history of infertility.     

Cytogenetic and histologic examination of four tortoiseshell cats

Tortoiseshell colored tomcats are very uncommon. In most cases their phenotype is caused by an aberration of sex chromosomes. In this study, we carried out cytogenetic investigations in four tortoiseshell tomacats. In two cases, an XXY syndrome could be proven. Another tortoiseshell tomcat had an XX/XY chromosomal constitution. One tomcat showed an exclusively male XY karyotype. In two cases the testes were histologically examined. In one XXY phenotypically male cat there was no spermatogenesis present. In the tomcat with XX/XY-chimerism spermatogenesis was seen in some testicular tubules.     

Polymorphism Analysis of Microsatellites Associated with Seven Candidate Genes for Equine Cryptorchidism

Association of seven candidate genes with cryptorchidism was investigated in the Thoroughbred. A pedigree composed of 23 cryptorchids and 24 nonaffected horses, sharing a common ancestor, was constituted. Sixteen microsatellite markers were developed either from bacterial artificial chromosomes (BAC) isolated for each candidate gene or by in silico screening. DNA from our pedigree was genotyped for these microsatellites. Statistical analysis of the allelic and genotypic frequencies observed with these markers did not reveal any association between the candidate genes and the cryptorchidism phenotype in our horse panel.     

Review and Update: Genomic and Molecular Advances in Sex Determination and Differentiation in Small Animals

Inherited disorders of sexual development are important to identify as a cause of inherited infertility or sterility in humans and animals. Investigation of these disorders in dogs and cats can identify new mutations, allowing us to eliminate inherited disorders from breeding populations, while contributing to the understanding of mammalian sexual development and differentiation. This review updates an overview of normal mammalian sexual development while discussing disorders of sexual development at three consecutive levels, as errors in sex chromosome constitution, gonadal sex determination or phenotypic sexual development. The molecular mechanisms controlling sexual development and current molecular methods to identify causative mutations are illustrated in three specific examples of abnormal sexual development reported in small animals: XX sex reversal, Persistent Mullerian Duct Syndrome and cryptorchidism. Identification of causative mutations and development of practical tests to identify carrier and affected animals will provide effective mechanisms to reduce the prevalence of these disorders in small animals.     

Candidate genes for physical performance in the horse

Intense selection for speed, endurance or pulling power in the domestic horse (Equus caballus) has resulted in a number of adaptive changes in the phenotype required for elite athletic performance. To date, studies in humans have revealed a large number of genes involved in elite athletic performance, but studies in horses are rare. The horse genome assembly and bioinformation tools for genome analyses have been used to compare human performance genes with their equine orthologues, both to retrieve pathways for these genes and to investigate their chromosomal distribution. In this review, 28 candidate genes for equine performance are presented that have polymorphisms associated with human elite athletic performance and may have impact on athletic performance in horses. A significant accumulation of candidate genes was found on horse chromosomes 4 and 12. Genes involved in pathways for focal adhesion, regulation of actin cytoskeleton, neuroactive ligand-receptor interaction, and calcium signalling were over-represented. Genome-wide association studies for athletic performance in horses may benefit from the strong conserved synteny of the chromosomal arrangement of genes in humans and horses.     

Ambiguous genitalia in a fertile, unilaterally cryptorchid male miniature schnauzer dog

A 7-year-old male miniature schnauzer dog with unilateral cryptorchidism was presented for elective orchiectomy. Surgery to remove the cryptorchid testis revealed a fully formed uterus with horns attached to both testis and the body and cervix terminating at the prostate gland. The gross and microscopic diagnosis for the genital tract was persistent Müllerian duct syndrome with unilateral cryptorchidism. Additional associated lesions included cystic endometrial hyperplasia and a solitary, intratubular seminoma within the undescended testis. Persistent Müllerian duct syndrome is rare among domestic animals but is more common in miniature schnauzer dogs because of inheritance as an autosomal recessive trait.     

An equine cryptorchid with testicular and ovarian tissues.

Cytogenetic and histological studies were carried out on an intersex horse which was diagnosed clinically as a cryptorchid. Surgery confirmed the horse to be a bilateral abdominal cryptorchid and histological examination revealed ovarian tissue associated with the left epididymis. Chromosome analysis of cultured cells from testicular tissue, ovarian tissue and skin revealed 64-XX and 64-XY make-up, the left gonad containing a greater preponderance of XX cells over XY cells. The external characteristics and behaviour of the horse were indistinguishable from that of a "routine" cryptorchid. Other cases of equine intersexes are reviewed and theories for the discrepancies between genetic, gonadal and phenotypic sex are discussed.     

First Description of Scrotal Testicles in a Dog Affected by 78, XX Testicular Disorder of Sex Development

An eight‐month‐old female dog presented with ambiguous external genitalia. A thorough clinical examination together with various imaging techniques and a histology examination showed the presence of two testicles linked to both the Mullerian and Wolffian ducts. The discovery of the 78,XX SRY‐negative karyotype led to the diagnosis of incoherence between the chromosomal and gonadal sex, which is typical for a 78,XX testicular disorder of sex development. Our case was unique because the testicles were still located in their normal scrotal position, whereas the literature contains reports of the presence of cryptorchid testicles in this karyotype setting. To our knowledge, this is the first case that describes an SRY‐negative 78,XX testicular disorder of sex development with bilateral scrotal testicles.     

Genes and respiratory disease: a first step on a long journey

This review highlights the critical importance of phenotype definition in the understanding of the pathogenesis of respiratory disease in horses. The general approach to genetic studies is discussed and comparative studies of recurrent airway obstruction (RAO) conditions, such as asthma, described in the context of learning more about equivalent equine conditions. The availability of methods to study genetic tests have previously relied on DNA sequence knowledge from man, laboratory and domesticated animals, but recent data from the horse genome sequence are now available. This should facilitate advances in the identification of specific genes for equine diseases. The review summarises the future potential for such studies and places the report in this issue (p 236) by Jost et al. (2007) of the involvement of IL4RA as a candidate gene in RAO into this context.     

78,XX testicular DSD syndrome in a mongrel dog

Because of an apparent sexual ambiguity (enlarged clitoris), a 1-year-old mongrel dog was presented to the clinic. A positive result on a GnRH stimulation test revealed the existence of functional testicular tissue. A midline laparotomy was performed, and gonads resembling testes were resected along with the adherent parts of the uterine horns. Microscopic examination confirmed that the sampled gonads were testes. Cross-sections of the head and tail of the epididymis revealed their typical structures. All layers of the uterine wall were well-developed. The lumen was stellar, covered by columnar cylindrical epithelium, although locally some epithelial cells had changed in height from columnar to flat. The uterine glands were distributed in functional layer of endometrium in a non-uniform way. Cytogenetic analysis based on the evaluation of metaphase plates of blood lymphocytes showed a female karyotype, 78,XX. PCR amplification of the SRY gene was negative in the studied mongrel dog. This canine disorder may be genetically heterogeneous, potentially with a different mutation in different breeds. An autosomal recessive inheritance for the XX male is suggested in such cases. The present case of sex reversal syndrome concerns a non-purebred dog. In mongrels, it is definitely less likely for the defect to be inherited because of a recessive disorder. According to the recently proposed nomenclature, the described case should be classified as 78,XX testicular DSD syndrome.     

XX/XY Blood Lymphocyte Chimerism in Heterosexual Dizygotic Twins from an American Bashkir Curly Horse. Case Report

Cytogenetic analysis and microsatellite genotyping were conducted on a pair of phenotypically normal dizygotic heterosexual equine twins of the American Bashkir Curly breed. The animals had a mixture of 64,XX and 64,XY cells in blood lymphocytes, with their own cells being predominant. Therefore, the 64,XX cells comprised 81% of the lymphocyte population in the female twin and 64,XY comprised 79% in the male twin. Blood chimerism was confirmed by genotyping 30 microsatellite markers. Of these, 15 microsatellites showed the presence of three alleles and all four parental alleles in the blood lymphocytes for both animals. No chimerism was detected in the genomic deoxyribonucleic acid isolated from hair follicles. These results are in agreement with earlier observations that vascular anastomoses can infrequently occur during equine multiple pregnancies resulting in blood lymphocyte chimerism without significant effect on the phenotype.     

The equine metabolic syndrome peripheral Cushing's syndrome.

Certain management practices tend to promote the development of obesity (metabolic syndrome) in mature horses as they enter their teenage years. These management practices include the provision of starch-rich (high glycemic index) and fat-supplemented rations to healthy horses that are relatively inactive. Some horse breeds and ponies appear to be genetically predisposed to metabolic syndrome. The accretion of intra-abdominal adiposity by equids is associated with the development of insulin insensitivity (hyperinsulinemia), glucose intolerance, dyslipidemia, hypertension, and insidious-onset laminitis. Omental adipocytes are metabolically active, secreting free fatty acids and hormonally active mediators including cortisol, leptin, and resistin that might contribute to persistence and worsening of insulin refractoriness and the obese phenotype. We have hypothesized that obesity-associated laminitis arises as a consequence of vascular changes and a hypercoagulable state, similar to the development of atherosclerosis in human type 2 diabetes. Several molecular mechanisms that might serve to explain the development of insulin insensitivity as a result of excessive adiposity have been incriminated. Little investigation into the relationship between obesity, insulin insensitivity, and laminitis in horses has been reported to date. Insulin sensitivity and glucose tolerance can be improved by dietary restriction and exercise aimed at reversing omental obesity. Management practices that promote the development of obesity are likely initiated during the first 10 years of the horse's life. Veterinarians and horse owners must recognize that mature-onset obesity in adult horses is associated with a risk for development of laminitis. Obesity and insulin insensitivity might be prevented if horse owners can be educated to feed rations with a relatively lower glycemic index to inactive horses. Investigative research pertaining to the development of antiobesity drugs for human patients is continuing. Greater than 30 new pharmaceuticals are in various stages of research. However, it will likely take many years before any of these drugs are shown to be useful and safe in horses. Lifestyle changes in the form of diet and exercise patterns are still the crux of therapy for both human and equine patients.     

Reproductive disorders in 10 domestic male cats

This study describes 10 tomcats with different reproductive disorders. Two of the cats had abnormal sex chromosomes; one was a tortoise-shell and white Cornish rex, while the other was a brown Burmese. The other eight cats were diagnosed as having testicular hypoplasia, diphallos in combination with unilateral cryptorchidism, a persistent penile frenulum, retrograde ejaculation, temporary oligozoospermia, teratozoosper-mia, azoospermia and congenital poor libido. For the cat with a persistent penile frenulum, and the cat with a temporary oligozoospermia, the prognosis for successful reproduction was considered favourable. By contrast it was considered unlikely that the cats with chromosomal abnormalities, testicular hypoplasia, diphallos, retrograde ejaculation, teratozoospermia and azoospermia would be able to produce offspring.     

A Review of Candidate Genes for Development of Equine Recurrent Uveitis

Equine recurrent uveitis (ERU) is a serious eye disease and the most common cause of blindness in horses. Until now, the cause of ERU is not fully understood. Persistent infections of pathogenic leptospires have been discussed. Chronic recurrent remitting episodes of inflammations and the positive therapeutic effects of corticosteroids have led to the hypothesis that ERU is an autoimmune disorder. The reason for a dysregulated autoimmune response may be linked to genetic factors. ERU shows similarities to human autoimmune uveitis with a genetic background. An association of the equine leukocyte antigen serological haplotype A9 with ERU in warmblood horses indicated that major histocompatibility complex I (MHCI) influences the development of ERU. The different types of human autoimmune and genetic uveitis, like Behçet's disease, systemic sarcoidosis, Vogt-Koyanagi-Harada syndrome, birdshot retinochoroidopathy, sympathetic ophthalmia, and acute recurrent anterior uveitis, had been associated with the human leukocyte antigen complex and genetic variants of the MHC. Furthermore non-MHC genes with a possible role in autoimmunity may also play a role in ERU-affected horses. The genes presented herein may be of interest for genome-wide association analyses of ERU-affected horses.     

Current concepts of hyperlipaemia in horses and ponies

Hyperlipaemia is an important condition in ponies, not just because of the seriousness of the clinical signs and biochemical changes involved, but because of the distress it causes owners and breeders that have had animals suffer from it. Hyperlipaemia occurs most commonly in fat ponies in late pregnancy and is rarely seen in larger horses. The syndrome has similarities with conditions in other species but the definitive aetiologies are not yet known. The condition in ponies is undoubtedly related to stress. The biochemical mechanisms involved in equine hyperlipaemia are considered and an hypothesis of possible pathogenesis is put forward. This hypothesis is tested by presenting the results of a preliminary study to evaluate glucose and lipid metabolism in horses and ponies. It appears that the pony is markedly insensitive to insulin compared to larger horses which means that triglycerides are more readily mobilised and the animal is therefore susceptible to hyperlipaemia in a situation of negative energy balance. The effect of stress is to increase cortisol levels which only exacerbates the insulin insensitivity and so creates a vicious circle. The importance of an innate insulin insensitivity may also be important in the pathogenesis of such conditions as laminitis.     

Sex Steroid Levels in XY Males and Sex‐Reversed XX Males,of Rainbow Trout (Oncorhynchus mykiss), During the Reproductive Cycle

In this study, the annual cycle of the gonadal steroids testosterone (T), 11‐ketotestosterone (11‐KT), 17β‐oestradiol (E2) and 17α, 20β‐dihydroxy‐4‐pregnen‐3‐one (DHP) was determined using radioimmunoassay and then compared, for XY males (n = 35) and sex‐reversed XX males (n = 27) rainbow trout, to establish possible endocrinology differences. Both in XY males and sex‐reversed XX males, significant correlation was shown between body weight and T (r = 0.5046 and 0.34078, respectively; p < 0.0001) or KT (r = 0.52494 and 0.43545, respectively; p < 0.0001) concentrations. Plasma androgen levels in XY and sex‐reversed XX males were similar and showed an intense seasonal variation. The highest levels for T and 11‐KT were detected from December to April with a peak in January (51.67 ± 5.11 and 61.95 ± 4.25 ng/ml, for XY males and 57.1 ± 5.82 and 59.27 ± 4.84 ng/ml, respectively, for XX males). In addition, there was a positive correlation (p < 0.0001) between T and 11‐KT levels for XY males (r = 0.7533) and sex‐reversed XX males (r = 0.6019). Concentrations of DHP in XY males also showed seasonal variation with a peak in February (25.18 ± 12.99 ng/ml). However, DHP levels in sex‐reversed XX males were undetectable (<0.1 ng/ml) over the year. Levels of E2 were undetectable through the year in both groups of trout. In conclusion, the androgenic and oestrogenic profiles of sex‐reversed XX males were similar to those observed in XY males. The only difference in the annual gonadal steroid cycle between XY and sex‐reversed XX males was in the DHP profile.     

Equine penile squamous cell carcinomas are associated with the presence of equine papillomavirus type 2 DNA sequences

Forty cases of equine penile disease were screened with polymerase chain reaction for the presence of papillomaviral DNA. Cases consisted of 20 squamous cell carcinomas (average age of horse, 23.9 years) and 20 non-squamous cell carcinoma diseases (average age of horse, 13.3 years). All horses but one originated from the Northeastern United States. Breeds were not recorded. As based on MY09/MY11 consensus primers, DNA sequences from equine papillomavirus type 2 were amplified from 9 of 20 horses (45%) with penile squamous cell carcinoma and only 1 of 20 horses (5%) with non-squamous cell carcinoma penile disease. Equine papillomavirus type 2 DNA was the only papillomaviral DNA amplified from any of the 40 horses. Tissues from the 10 horses in which papillomaviral DNA was detected by polymerase chain reaction were also screened with in situ hybridization and immunohistochemistry. The presence of papillomavirus was demonstrated in a subset of these by in situ hybridization (6 of 10) and immunohistochemistry (1 of 10). This report describes a possible association between equine penile squamous cell carcinomas and equine papillomavirus type 2. This study is also the first report of equine papillomavirus type 2 infection in North American horses.