46,XY complete gonadal dysgenesis (ORPHA:242)
A rare disorder/difference of sex development (DSD) associated with absence in gonadal development that results in the presence of female appearing external and internal genitalia in presence of a 46,XY karyotype.
Epidemiology
The prevalence of 46,XY complete gonadal dysgenesis ( 46,XY CGD) is unknown.
Clinical description
Patients are born with typical female appearing external genitalia as well as the presence of a uterus and fallopian tubes. They often present during adolescence or early adulthood with lack of pubertal development although adrenarche is normal. Completely undeveloped streak gonads are present and are associated with an increased risk of abdominal tumors (most commonly dysgerminoma), which may be the presenting feature in some cases. Stature is normal or above normal, and features of Turner syndrome are absent.
Etiology
Although the etiology is not completely understood, 46,XY CGD results from failure of testicular development due to disruption of the underlying genetic pathways. Several genes have been implicated: SRY (gene deletion 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) 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 (5q11.2) that cause downstream alterations in the MAP kinase signaling pathway have recently been identified in two familial and two sporadic cases. Of high clinical relevance, 46,XY CGD is a feature of Frasier syndrome (caused by WT1 variants). Environmental factors (maternal progesterone intake during pregnancy), and impaired prenatal growth have also been associated with 46,XY CGD. In the majority of cases, the genetic etiology remains unclear.
Diagnostic methods
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.
Differential diagnosis
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).
Antenatal diagnosis
Prenatal diagnosis is feasible for families in which the genetic anomaly has been confirmed but is only recommended in syndromic cases.
Genetic counseling
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 and treatment
Management may involve removal of streak gonadal tissue as there is a risk for malignancy, which may depend on the underlying etiology. 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 in a specialized DSD-center. Infertility is an important management issue; however, pregnancy may be feasible through zygote egg donation.
Prognosis
With appropriate management, the risk of malignancy is low and the psychological and clinical outcome for patients is good.

                            Last update: 
                            June 2022


                            - Expert reviewer(s): 
                            Pr Olaf HIORT | Endo-ERN*


                                * European Reference Network