Equis ISSN 2398-2977

Reproduction: gonadal dysgenesis

Contributor(s): Terry Blanchard, William Ley, Graham Munroe, Sarah Stoneham, Madeleine L H Campbell

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.

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

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Treatment

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Prevention

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Outcomes

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Further Reading

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