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46,XX gonadal dysgenesis
Disease definition
A rare disorder/difference of sex development characterized by a primary ovarian defect, either a failure of the gonads to develop or resistance to gonadotrophin stimulation which leads to premature ovarian failure (POF) in otherwise phenotypically female 46,XX individuals.
ORPHA:243
Classification level: Disorder- Synonym(s):
- 46,XX complete gonadal dysgenesis
- 46,XX ovarian dysgenesis
- 46,XX pure gonadal dysgenesis
- Hypergonadotropic ovarian dysgenesis
- XX female gonadal dysgenesis
- XX-GD
- Prevalence: 1-9 / 100 000
- Inheritance: Autosomal dominant or Autosomal recessive or X-linked recessive or Not applicable
- Age of onset: Adolescent, Adult
- ICD-10: Q99.1
- ICD-11: LB45.1
- OMIM: 233300 300510 614324 618078 618117 618723
- UMLS: C0949595
- MeSH: D023961
- GARD: -
- MedDRA: -
Summary
Epidemiology
Prevalence is unknown.
Clinical description
Patients are born with typical female sex characteristics without ambiguity. However, affected individuals present during adolescence or young adulthood with either delayed or absent puberty resulting in primary or sometimes secondary amenorrhea. The internal and external genitalia are typically developed. 46,XX gonadal dysgenesis can occur as part of Perrault syndrome (ovarian dysgenesis and deafness with or without cerebellar ataxia), as well as other rare syndromes such as lung fibrosis-immunodeficiency-gonadal dysgenesis.
Etiology
Ovarian dysgenesis results from genetic defects of ovarian development. Although the underlying etiology remains unknown in most cases, several genes have been implicated including homozygous or compound heterozygous inactivating mutations of the follicle-stimulating hormone receptor gene (FSHR; 2p21-p16), mutations in the BMP15 gene (Xp11.2) and mutations in the NR5A1 gene (9q33), amongst others.
Diagnostic methods
Diagnosis requires an evaluation of hormonal status (gonadal and adrenal), laboratory investigations to screen for infectious or autoimmune disorders, karyotype analysis, molecular studies and sometimes laparoscopy with biopsy of ovarian tissue.
Differential diagnosis
The differential diagnosis should include other causes of POF, as well as 46,XY complete gonadal dysgenesis. In addition, secondary ovarian hypoplasia has been described in association with infectious agents (HIV) or autoimmunity (APECED syndrome associated with AIRE gene mutations).
Antenatal diagnosis
Prenatal molecular diagnosis is feasible in cases where a mutation has been identified in the family.
Genetic counseling
Genetic counseling may be offered. Inactivating FSHR mutations are inherited in an autosomal recessive manner, BMP15 mutations are inherited in an X-linked manner and NR5A1 mutations are autosomal dominant in the great majority of cases.
Management and treatment
Management should include hormone replacement therapy. Calcium and vitamin D supplements may also be proposed. Psychological support should also be offered to patients and their families in a disorder of sexual development-center setting. Infertility is an important management issue; however, pregnancy may be feasible through zygote egg donation.
Prognosis
With appropriate management, the physiological and clinical outcome for patients is good.
A summary on this disease is available in Español (2022) Français (2022) Nederlands (2022) Deutsch (2011) Italiano (2011) Português (2011) Greek (2011, pdf) Suomi (2011, pdf) Polski (2011, pdf)
Detailed information
Disease review articles
- Review article
- English (2012) - RadioGraphics
Genetic Testing
- Guidance for genetic testing
- Français (2016, pdf) - ANPGM
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: produced/endorsed by FSMR(s)Additional information