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46,XY complete gonadal dysgenesis

ORPHA242
Synonym(s) 46,XY CGD
46,XY pure gonadal dysgenesis
Swyer syndrome
Prevalence Unknown
Inheritance Autosomal dominant
or Autosomal recessive
Age of onset Adolescent
Adult
ICD-10
  • Q97.3
OMIM
UMLS
  • C2936694
MeSH -
MedDRA -

Summary

46,XY complete gonadal dysgenesis (46,XY CGD) is a disorder of sex development (DSD) associated with anomalies in gonadal development that result in the presence of female external and internal genitalia despite the 46,XY karyotype.

The prevalence is unknown.

Patients present during adolescence or early adulthood with normal female external genitalia but lack pubertal development although adrenarche is normal. Completely undeveloped streak gonads are present and are associated with an increased risk of abdominal tumours (most commonly dysgerminoma; see this term), which may be the presenting feature in some cases. Stature is normal or above normal, and features of Turner syndrome (see this term) are absent.

Although the etiology is not completely understood, 46,XY CGD results from failure of testicular development due to disruption of the underlying genetic pathways and several genes have been implicated: SRY (gene deletion of or loss-of-function mutations; Yp11.3), NR5A1 (9q33) and DHH (homozygous or compound heterozygous mutations; 12q13.1). In addition, patients with partial duplications of Xp (including the NR0B1 gene) and chromosome 9p deletions (involving the DMRT1 and DMRT2 genes) may also present with isolated 46, XY CGD. Mutations in the CBX2 gene have been rarely reported, namely in a patient with development of ovarian tissue despite 46,XY karyotype. Mutations in the MAP3K1 gene (mapped on chromosome 5q) that cause downstream alterations in the MAP kinase signaling pathway have recently been identified in two familial and two sporadic cases. Environmental factors (maternal progesterone intake during pregnancy), and impaired prenatal growth have also been associated with 46,XY CGD.

Diagnosis is made on the basis of the clinical findings together with cytogenetic analysis, endocrine investigations, molecular genetic studies, and sometimes surgical exploration with biopsy and removal of streak gonads.

The differential diagnosis should include hypergonadotropic ovarian dysgenesis (46,XX GD) and all forms of syndromic 46,XY CGD (for example, Frasier syndrome, campomelic dysplasia and 46,XY DSD with adrenal insufficiency; see these terms).

Prenatal diagnosis is feasible for families in which the genetic anomaly has been confirmed but is only recommended in syndromic cases.

Although some cases of 46,XY CGD occur sporadically, genetic counseling may be offered to affected families and should be adapted depending on the mode of inheritance associated with the genetic anomaly identified.

Management should involve removal of streak gonadal tissue as there is a high risk for malignancy. Possible associated health issues (e.g. associated malformations) need to be addressed according to the genetic diagnosis. Hormone substitution is recommended at the time of puberty. 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 risk of malignancy is low and the psychological and clinical outcome for patients is good.

Expert reviewer(s)

  • Pr Olaf HIORT

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Detailed information

Summary information
Clinical genetics review
  • EN (2009)
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