46,XX DSD can be classified into disorders of ovarian development, conditions with androgen excess and other syndromes, which are often associated with other developmental abnormalities.
21-hydroxylase deficiency CAH with androgen excess is the commonest cause of 46, XX DSD with atypical genitalia in the neonatal period or early infancy and is characterized by androgen excess and a variable alteration in glucocorticoid and mineralocorticoid function and a specific profile of steroid hormones.[86,87] This profile can identify the enzyme defects including deficiency of 21-hydroxylase (90%–95% of cases), 11β-hydroxylase (4%–8% of cases), 3β-hydroxysteroid dehydrogenase type 2 (rare) and P450 oxidoreductase (unknown prevalence). P450 oxidoreductase deficiency (PORD) biochemically manifests as apparent combined CYP17A1 and CYP21A2 deficiency, sometimes also resembling CYP19A1 (aromatase) deficiency. Unlike other forms of CAH, PORD is characterized by increased androgen concentrations only during the prenatal and early neonatal period, but rapidly develop sex hormone deficiency. Further details of these enzyme defects as well as others that can cause 46, XX DSD are outlined in Table 2.
46, XX DSD also includes disorders of gonadal development including 46, XX ovotesticular DSD and 46, XX testicular DSD. 46, XX ovotesticular DSD commonly presents at birth with atypical genitalia and progressive virilization during puberty. In contrast, individuals with 46, XX testicular DSD usually have a male phenotype and absent Müllerian structures and are often diagnosed after karyotype analysis during work-up for infertility. In 46, XX testicular DSD, about 80%–90% of patients will have Y chromosomal material including a translocated SRY gene, which is only rarely detected in 46, XX ovotesticular DSD. In other cases of 46, XX testicular DSD, duplications involving regulatory genes, SOX9 and SOX3 have been described. Gene variants in NR5A1 and NR2F2 have also been reported in 46, XX testicular and ovotesticular DSD with the NR2F2 variants being associated with cardiac defects as well as other features. Rarely, RSPO1 and WNT4, and more recently WT1 variants have also been described.[89,90] In those with a suspicion of 46, XX ovotesticular DSD, functional testing will require detection of testicular and ovarian tissue by a combination of biochemical testing, imaging and surgical exploration.
Disorders of Müllerian development are another group of 46, XX DSD, and in these cases, ovarian function is usually normal but often associated with cloacal anomalies and other characteristic malformations. Novel and recurrent copy number variations have been reported to be associated with a third of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome and other Müllerian abnormalities.[91,92] Although most cases of Müllerian development disorders are not associated with androgen excess, the presence of the latter, particularly in the adolescent, should alert the clinician to a possible abnormality of the WNT4 gene. Variants in a wide range of genes have now been described to be associated with uterine abnormalities and often these conditions are associated with multiple other anomalies.
Clin Endocrinol. 2021;95(6):818-840. © 2021 Blackwell Publishing