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46,XX gonadal dysgenesis

Orpha number ORPHA243
Synonym(s) 46,XX complete gonadal dysgenesis
46,XX ovarian dysgenesis
46,XX pure gonadal dysgenesis
FSH-RO
Follicular stimulating hormone-resistant ovaries
Hypergonadotropic ovarian dysgenesis
XX female gonadal dysgenesis
XX-GD
Prevalence 1-9 / 100 000
Inheritance Autosomal dominant
X-linked recessive
Not applicable
Autosomal recessive
Age of onset Adolescent
Adult
ICD-10
  • Q99.1
ICD-O -
OMIM
UMLS
  • C0685837
  • C0949595
MeSH
  • D023961
MedDRA -

Summary

46,XX gonadal dysgenesis (46,XX GD) is a primary ovarian defect leading to premature ovarian failure (POF; see this term) in otherwise normal 46,XX females as a result of failure of the gonads to develop or due to resistance to gonadotrophin stimulation.

Prevalence is unknown but is thought to be less than 1/10,000.

Patients are born as females 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 normally developed. Associated findings occur infrequently: deafness with or without cerebellar ataxia (Perrault syndrome; see this term), as well as other rare syndromes (lung fibrosis-immunodeficiency-gonadal dysgenesis; see this term).

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). 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.

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.

The differential diagnosis should include other causes of POF, as well as 46,XY complete gonadal dysgenesis (see these terms). In addition, secondary ovarian hypoplasia has been described in association with infectious agents (HIV) or autoimmunity (APECED syndrome associated with AIRE gene mutations; see this term).

Prenatal molecular diagnosis is feasible in cases where a mutation has been identified.

Genetic counseling may be offered.

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. Infertility is an important management issue; however, pregnancy may be feasible through zygote egg donation.

With appropriate management, the physiological and clinical outcome for patients is good.

Expert reviewer(s)

  • Pr Olaf HIORT
  • Pr Peter WIEACKER

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