46,XX Gonadal Dysgenesis

46,XX gonadal dysgenesis is a disorder present in individuals who are phenotypic females with normal karyotypes of 46,XX and who have streak gonads with no functional ovarian tissue. It is also called “pure gonadal dysgenesis” to differentiate these patients from those who present with the phenotype of Turner’s syndrome (webbed neck, short stature, widely spaced nipples). Patients present with a normal development during childhood, primary amenorrhea, infertility, and a lack of secondary sexual characteristics. Management includes hormone replacement therapy and prophylactic gonadectomy.

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Etiology and Pathophysiology

Synonyms

  • Ovarian dysgenesis 1 (ODG-1)
  • Hypergonadotropic ovarian dysgenesis
  • Pure gonadal dysgenesis
  • 46,XX ovarian dysgenesis
  • Hypergonadotropic ovarian failure

Epidemiology

  • Very rare
  • Incidence is thought to be < 1 case per 10,000 individuals

Etiology

  • Karyotype of an individual with pure gonadal dysgenesis is 46,XX
  • Caused by homozygous or compound heterozygous mutation in the gene-encoding follicle-stimulating hormone receptor (FSHR) on chromosome 2p16
  • Various genetic defects are known:
    • Autosomal recessive mutations that inactivate the FSHR gene 
    • X-linked mutations in the BMP15 gene
    • Autosomal dominant mutations in the NR5A1 gene

Pathophysiology

Various mutations (especially point mutations that lead to FSH-resistant ovaries) lead to interrupted ovarian development during embryogenesis OR premature depletion of ovarian follicles → impaired estrogen secretion → undeveloped secondary sexual characteristics.

Clinical Presentation

  •  Phenotype:
    • Childhood: normal development of female genital organs
    • Puberty: undeveloped secondary sexual characteristics
  • Cognition/intelligence: normal
  • Behavioral phenotype: normal
  • Sex development/fertility: 
    • Infertility
    • Primary amenorrhea
  • Perrault syndrome: ovarian dysgenesis with sensorineural deafness
    • Hearing loss
    • Intellectual disability
    • Ataxia (difficulty with balance and coordination)
    • Peripheral neuropathy

Diagnosis and Management

Diagnosis

Diagnosis is mainly clinical, based on amenorrhea, undeveloped secondary sexual characteristics, and a lack of the typical phenotype of Turner’s syndrome.

  • Hormonal testing:
    • ↑ gonadotropins
    • ↓ estrogen
  • Karyotype testing: confirms 46,XX normal female karyotype
  • Imaging of the pelvis shows presence of a normal or small uterus and no ovaries.

Management

  • Lifelong hormonal therapy of estrogen and progesterone substitution:
    • Primarily indicated to stimulate the development of secondary sexual characteristics and restore a regular menstrual cycle 
    • Cannot prevent infertility, since it has no effect on the FSH resistance responsible for premature ovarian failure
  • Fertility treatment: oocyte donation and hormonal therapy

Differential Diagnosis

The following conditions are differential diagnoses for pure gonadal dysgenesis.

  • Turner syndrome: a gonosomal monosomy of the X-chromosome, resulting in a karyotype of 45,X0 and a female phenotype. Patients usually present with amenorrhoea, webbed neck, short stature, infertility, intellectual deficit, and wide-spaced nipples. 
  • Swyer syndrome: a disorder of sex development caused by a defect in the SRY gene on chromosome Y. Characterized by complete testicular dysgenesis in an individual who has a 46,XY karyotype and is phenotypically female. Presents as a phenotypic female, taller than an individual with 46,XX gonadal dysgenesis, with a normal childhood and development until puberty, which is characterized by primary amenorrhea and no development of secondary sexual characteristics.

References

  1. O’Neill MJF. Ovarian Dysgenesis 1. (2018). Online Mendelian Inheritance in Man, An Online Catalog of Human Genes and Genetic Disorders. https://www.omim.org/entry/233300#
  2. O’Neill MJF, Bocchini CA. (Last edit:  August 2019). 46,XY Gonadal Dysgenesis, Complete, Sry-Related. Online Mendelian Inheritance in Man, An Online Catalog of Human Genes and Genetic Disorders. https://www.omim.org/entry/400044?search=swyer&highlight=swyer
  3. Moshiri M, Chapman T, Fechner PY. (2012). Evaluation and Management of Disorders of Sex Development: Multidisciplinary Approach to a Complex Diagnosis. RadioGraphics 2012; 32:1599–1618. DOI: 10.1148/rg.326125507.
  4. Orphanet. 46,XX gonadal dysgenesis. Retrieved on August 15, 2020 from https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=1011&MISSING%20CONTENT=46-XX-gonadal-dysgenesis&search=Disease_Search_Simple&title=46,XX%20gonadal%20dysgenesis

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