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Reproduction: gonadal dysgenesis

ISSN 2398-2977


Introduction

  • Gonadal dysgenesis results from chromosomal abnormalities in females.
  • Cause: genetic abnormality of the chromosome resulting in range of phenotypic abnormalities of the genitalia. Most commonly reported chromosome abnormality is 63XO (missing sex chromosome). Klinefelter's syndrome (rare) occurs when an extra X chromosome occurs with an XY, ie XXY; the individual is phenotypically male. Intersex occurs in XX females with masculinizing gene either mutated or collected from the Y chromosome.
  • Signs: depends on the chromosomal abnormality.
  • Diagnosis: full clinical fertility examination, palpation per rectum, blood testing.
  • Treatment: no treatment is possible.
  • Prognosis: confirmed gonadal dysgenesis are usually infertile; some mosaic types may be capable of limited breeding.

Presenting signs

  • Depends on the chromosomal abnormality.
  • 63XO:
    • Anestrus.
    • Infantile tubular tract and ovaries.
    • External genitalia often normal.
    • Animal smaller than usual for breed, but not always; sometimes they appear phenotypically normal.
  • Intersex horses (XX-sex reversal) have three main sexually ambiguous phenotypes:
    • XX-male - male with small, usually undescended, testes, no sperm and reduced libido.
    • XX-male - pseudohermaphrodite - abdominal or inguinal inactive testes, enlarged clitoris and male attitude.
    • XX-true hermaphrodite - female with abdominal testis and ovary (ovotestes), enlarged clitoris and maybe male attitude.

Geographic incidence

  • Worldwide.

Age predisposition

  • Congenital; detected at breeding age.

Breed/Species predisposition

  • Reported in all breeds.

Cost considerations

  • Results in infertility and loss of mare from breeding program.

Pathogenesis

Etiology

  • Abnormal chromosome number or structure resulting from non-dysjunction or error in chromosome division, during meiotic division of either gamete or in mitosis after fertilization.
  • A numeric abnormality: can be missing (monosomy) or extra (trisomy) chromosomes.
  • Structural anomalies include inversions, reciprocal translocations, centric fusions and partial deletions.
  • The diploid chromosome number of the horse is 64, made up of 31 autosomal pairs, and 2 sex chromosomes (XX or XY).
  • The most common chromosomal abnormality (up to 50% of cases) in horses is 63XO, ie a missing X chromosome.
    • The lack of one chromosome is called a 'monosomy'.
    • In humans, the condition of females missing one X chromosome is referred to as 'Turners syndrome'.
    • 63XO mares are therefore often referred to as 'Turners mares', although phenotypic effects of being XO are not as severe in mares as they are in humans.
    • About 15% of 'Turner mares' are mosaics, ie there are at least 2 different cell populations present within an individual - some 63XO cells, and some 64XX or 64XY cells.
    • 63XO mares are infertile.
  • The second most common chromosomal abnormality (up to 40% of cases of sex chromosome abnormality in horses) is 64XY sex reversal syndrome, in which the phenotypic sex does not coincide with the chromosomal sex. Many of these animals have gonadal dysgenesis or 'testicular feminization' and, unlike monosomy, they are heritable.
  • Other chromosomal abnormalities occurring in horses include:
    • 64XX, delXp where a portion of the short (p) arm of one X chromosome is deleted.
    • 65XXXtrisomies.
    • Other mosaics such as 64XX/65XXX.

Predisposing factors

Specific

  • Congenital condition manifested in adulthood.

Pathophysiology

  • Initiation of gonad formation requires only one X or one Y chromosome.
  • Completion of normal gonadal development requires that germ cells in the ovary have XX chromosomes and in the testis XY.
  • A signal from the Y chromosome (testis determining factor, TDF) converts undifferentiated gonads into testes. Absence of TDF results in ovarian formation.
  • However, many genes are required in the pathway leading to correct gonad formation and abnormalities such as sex reversal syndrome can result when any of these genes is prevented from functioning in an XY embryo or is gratuitously induced in an XX embryo.
  • Malsegregation of the sex chromosome during gametogenesis → non-mosaic sex chromosome abnormalities.
  • Abnormal number and/or structure of chromosomes in mare, eg 63XO → infantile reproductive organs and infertility.
  • XXY (Klinefelter's syndrome) affects fertility and growth rate because some genes in the extra X chromosome escape the inactivation process:
    • The extra X chromosome in Klinefelter's inhibits testicular development and spermatogenesis.
  • Intersex is an XX-sex reversal (female → male phenotype):
    • There is an abnormal X-Y interchange during spermatogenesis usually resulting in the transfer of the masculinizing SRY gene from the Y to the X chromosome, ie affected horses are SRY positive.
    • Some intersex horses are SRY negative, and the abnormality is considered to be an heritable, recessive, autosomal gene mutation acting as the initiator of testicular determination.
    • Appearance (phenotype) depends on the amount of testicular tissue present.
  • XXY aneuploidy in horses is rare compared to humans.
  • Chromosomal abnormalities → low progesterone and estrogen levels → lack of negative feedback on hypothalamus → elevated luteinizing hormone in some cases.
  • Chromosomal abnormalities → persistently low progesterone and estrogen levels → infantile reproductive tract → extreme endometrial epithelial and glandular hypoplasia   Endometrium: hypoplasia → infertility.

Timecourse

  • Congenital defect.

Diagnosis

Presenting problems

  • Failure to cycle.
  • Infertility.

Client history

  • Depends on the underlying chromosomal abnormality.
  • Infertility.
  • Anestrus or abnormal cycling behavioral signs.
  • Passive behavior, some sexual receptivity or outright rejection.
  • Small for breed especially in XO monosomy.
  • Masculinized mare (XY sex reversal).

Clinical signs

  • Intersex horses display a range of phenotypes from (almost) complete male to complete female:
    • The most common presentation of intersex is a mare with an enlarged clitoris and variously developed abdominal or inguinal testes.
    • XXY syndrome results in inhibited testicular development - not evident before puberty.
    • Aggressive or male behavior.
    • External genitalia normal although vulva may be small. No clitoral enlargement.
  • XO mares are typically small for breed and may have overall poor conformation Musculoskeletal: conformation.
  • Phenotypic expression in XY sex reversal syndrome is highly variable - feminine to masculine mare.
  • XXY mosaics and XY sex reversal may show masculine features; occasional XY sex reversal cases are fertile.
  • Other chromosomal abnormalities are phenotypically similar to X monosomy although occasionally they have functional ovaries, ovulate and even conceive.

Diagnostic investigation

Some XO mosaic mares may be palpably normal.

Other

  • A heparinized blood sample to allow cytogenic analysis of chromosomes from cultured cells arrested in metaphase of mitosis.
  • Leukocyte karyotyping is essential to confirm diagnosis and prognosis.

Confirmation of diagnosis

Discriminatory diagnostic features

Definitive diagnostic features

  • Karyotyping.

Gross autopsy findings

  • Small or non-existent ovaries.
  • Lack follicular development and no functional germinal tissue. In XY reversal mares the gonads may have histologic characteristics of both ovaries and testes.
  • Small flaccid reproductive tract or vestigial remnant.
  • Normal external genitalia.

Histopathology findings

  • Extreme endometrial epithelial and glandular hypoplasia.

Differential diagnosis

Treatment

Initial symptomatic treatment

  • No treatment is possible.

Prevention

Control

  • Gene mapping and pedigree studies:
    • For intersex cases that are SRY negative, the mutated gene is probably inherited as a recessive trait, ie an affected filly would have two mutated genes, one from each parent.
    • Heterozygous females would be phenotypically normal, but carriers of one mutated gene.
    • Males are phenotypically normal even if homozygous for the mutated gene because normal SRY gene on the Y chromosome usually results in normal testicular development.

Outcomes

Prognosis

  • Mares with confirmed gonadal dysgenesis, especially 63XO, are usually infertile but occasional cases have been reported as fertile.
  • Some mosaic types may be capable of limited breeding.

Reasons for treatment failure

  • Most mares with this condition are infertile.

Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Anaya G et al (2014) Sex reversal syndrome in the horse: four new cases of feminization in individuals carrying a 64,XY SRY negative chromosomal complement. Anim Repro Sci 151 (1-2), 22-27 PubMed.
  • Card C (2012) Congenital abnormalities of the cervix in mares. Equine Vet Educ 24 (7), 347-350 VetMedResource.
  • Makinen A et al (2000) Two sterile stallions with XXY-syndrome. Equine Vet J 32 (4), 358-360 PubMed.
  • Buoen L C et al (2000) SRY-negative, XX intersex horses: the need for pedigree studies to examine the mode of inheritance of the condition. Equine Vet J 32 (1), 78-81 PubMed.
  • Abe S, Miyake Y-I, Kageyama S-I et al (1999) Deletion of the Sry region of the Y chromosome detected in a case of equine gonadal hypoplasia (XY female) with abnormal hormone profiles. Equine Vet J 31 (4), 336-338 PubMed.
  • Makinen A, Hasegawa T, Makila M & Katila T (1999) Infertility in two mares with XY and XXX sex chromosomes. Equine Vet J 31 (4), 346-349 PubMed.
  • Gill J J B, Kempski H M, Hallows B J & Warren A M (1988) A 64XX/65XXX mosaic mare (Equus caballus) and associated infertility. Equine Vet J 20 (2), 128-130 PubMed.
  • Gill J J B (1988) Editorial - Sex chromosomes of horses; or what the X happening? Equine Vet J 20 (2), 81-82 PubMed.
  • Long S E (1988) Chromosome anomalies and infertility in the mare. Equine Vet J 20 (2), 89-93 PubMed.
  • Bowling A T, Millon L & Hughes J P (1987) An update of chromosomal abnormalities in the mare. J Reprod Fertil Supp 35, 149-155 PubMed.
  • Power M M (1986) XY sex reversal in a mare. Equine Vet J 18 (3), 233-236 PubMed.

Other sources of information

  • Lear T L & Villagomez A F (2011) Cytogenic evaluation of mares and foals. In: Equine Reproduction. Eds: McKinnon A O, Squires E L, Varner W E & Varner D D. Blackwell Publishing Ltd. pp 1951-1961.
  • Troedsson M H T & Barber J A (1997) Diseases of the Ovary. In: Current Therapy in Equine Medicine. 4th edn. Ed: N E Robinson. Saunders and Co, USA.