Etiology and Pathophysiology
- Ovarian dysgenesis 1 (ODG-1)
- Hypergonadotropic ovarian dysgenesis
- Pure gonadal dysgenesis
- 46,XX ovarian dysgenesis
- Hypergonadotropic ovarian failure
- Very rare
- Incidence is thought to be < 1 case per 10,000 individuals
- 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
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.
- Childhood: normal development of female genital organs
- Puberty: undeveloped secondary sexual characteristics
- Cognition/intelligence: normal
- Behavioral phenotype: normal
- Sex development/fertility:
- 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 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.
- 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
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.
- 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#
- 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
- 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.
- 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