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45,X/46,XY mixed gonadal dysgenesis
45,X/46,XY mixed gonadal dysgenesis (45,X/46,XY MGD) is a disorder of sex development (DSD) associated with a numerical sex chromosome abnormality resulting from Y-chromosome mosaicism and leading to abnormal gonadal development.
ORPHA:1772Classification level: Disorder
- 45,X/46,XY MGD
- 45,X0/46,XY MGD
- 45,X0/46,XY mixed gonadal dysgenesis
- Prevalence: Unknown
- Inheritance: Not applicable or Unknown
- Age of onset: All ages
- ICD-10: Q98.7
- OMIM: -
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
Prevalence is unknown.
The clinical manifestations are highly variable, ranging from partial virilisation and ambiguous genitalia at birth to patients with a completely male or female phenotype. The most common feature of MGD is asymmetric development of testes, often with a dysgenetic testis on one side and a streak gonad on the other. Asymmetry of the external and internal genitalia may also be present. Infants with male sex assignment may present with cryptorchidism, partial testicular dysgenesis, and hypospadias. There is usually persistence of müllerian structures. Infants with female sex assignment present with varying degrees of virilization and may show manifestations of other clinical features of Turner syndrome (see this term). The uterus is of variable size and the degree of differentiation of the internal genitalia varies. Short stature may be present in both sexes and patients are at increased risk of developing gonadoblastomas and dysgerminomas (see these terms). Psychomotor development is normal.
Patients with 45,X/46,XY MGD mostly have a 45,X/46,XY karyotype, with the phenotype of the gonads and the external genitalia depending on the proportion of monosomic cells. The presence of 45,X cell lines is frequently associated with Y chromosome rearrangements (commonly dicentric and ring Y chromosomes), which may also have an impact on the phenotype. All cases are sporadic. Several genotype-phenotype correlations have been established: partial expression of the SRY gene (leading to partial testicular dysgenesis and resulting in diminished testosterone synthesis and hence to the virilisation deficit), presence of the gonadoblastoma (TSPY1) locus on the Y-chromosome in females (associated with an increased risk for the development of neoplasms), and dosage loss of the SHOX gene leading to short stature. The formation of the uterus is due to lack of production of anti-Müllerian hormone.
Diagnosis is made by cytogenetic analysis of chromosome status. Karyotype analysis may be conducted prenatally after amniocentesis or chorionic villus sampling, postnatally in patients with ambiguous genitalia, or later in life in patients with fertility problems.
The differential diagnosis should include 46,XY partial gonadal dysgenesis (46,XY PGD; see this term) and syndromic 46,XY gonadal dysgenesis (such as Frasier syndrome, campomelic dysplasia and 46,XY DSD with adrenal insufficiency; see these terms).
Antenatal diagnosis is possible if a genital malformation is suspected with imaging.
Genetic counseling should be provided to parents with a prenatal diagnosis of 45,X/46,XY mosaicism but is complicated by the broad phenotypic spectrum associated with this anomaly.
Management and treatment
Multidisciplinary management in a centre for DSDs should be favoured in cases of obvious ambiguous genitalia, allowing informed decisions for sex assignment and planning of procedures. Surgical reconstruction of genital status should be performed in due course. Gonadectomy may be favoured in patients with a female sex assignment due to the increased risk of gonadoblastoma. In patients with male sex assignment, orchidopexy is required for fixation of the testes in the scrotum and biopsy may be recommended at the time of puberty. Usually, the more dysgenetic gonad needs to be removed. Due to the increased risk of malignancy, ultrasound of the gonads should be performed on a regular basis. In some patients, the possibility of growth hormone treatment needs to be discussed if short stature is found.
Clinical and psychological outcomes depend on the quality of care and level support provided.