synthesis of sex steroids by the gonads and adrenals. With 3‐ ß‐hydroxysteroid deficiency, the only androgen synthesised is dehydroepiandrosterone (DHEA), which is relatively weak, and females with this deficiency are less virilised than those with the 21‐ or 11‐ß ‐hydroxylase deficient forms of CAH. With reduced levels of 17‐hydroxysteroid dehydrogenase, the female external genitalia are normal at birth, but no secondary sexual development occurs at puberty.
Maternal androgen excess
In rare instances, virilisation of the female foetus may occur if the mother is suffering from certain ovarian or adrenal tumours or if she has unrecognised CAH. The absence of virilisation in the mother does not exclude a maternal source of androgens since the level of androgen required to change the external genitalia of the early female foetus is much less than would be required to have the same effect on the adult female [34].
Exogenous androgen excess
Virilisation of the external genitalia of female infants has been frequently observed following maternal ingestion of testosterone or synthetic progestational agents during the first trimester of pregnancy [35]. Administration of such agents between the 8th and 12th weeks of gestation causes marked virilisation, but later in pregnancy they cause clitoral enlargement. These agents, as well as stilboestrol, were often prescribed in the past for women with recurrent miscarriage. Exposure to stilboestrol during intrauterine life is known to cause malformations in the reproductive tracts of both sexes, 46,XX DSD, and an increased incidence of cervical and vaginal neoplasia [36].
Intrauterine exposure to danazol, used in the treatment of endometriosis, has also been associated with virilisation of the female foetus, and in one study of 94 completed pregnancies in women taking danazol, 23 of the female offspring had genital abnormalities including clitoromegaly and fused labia [37].
Maternal cocaine use during pregnancy has been linked with ambiguous genitalia in both male and female infants, as well as other congenital malformations [38].
46,XY DSD
These disorders relate to patients with abnormalities of testicular differentiation or androgen synthesis or activity. The most common disorder of androgen synthesis is 5∝‐reductase deficiency secondary to mutations in the SRD5A2 gene. This enzyme is involved in the virilisation of the external genitalia during embryogenesis. The genitalia are ambiguous at birth, but at puberty can develop further male characteristics.
Androgen insensitivity syndromes, complete or partial, are due to a mutation in the androgen receptor genes leading to hormone resistance in the presence of a 46,XY karyotype. In the complete form, there are no functional androgen receptors. The external genitalia are female, but the Müllerian structures are absent and patients most frequently present with failure of menstruation. There is a blind‐ending vagina and bilateral testes, usually in the abdomen or inguinal canal. As systemic oestrogen is present, secondary sexual characteristics do appear, but pubic hair is sparse or absent. There is an increased risk of testicular neoplasia, and the testes are usually removed after puberty.
In partial forms of androgen insensitivity, there is some androgen receptor function, and although the external genitalia are female, there is a degree of virilisation at puberty which may include phallic enlargement and labioscrotal fusion.
Disorders of gonadal development
Complete or partial gonadal dysgenesis
These patients have a 46,XY karyotype, but do not possess any gonadal tissue. It is characterised by the presence of ambiguous genitalia in association with hypoplastic Müllerian and Wolffian derivatives. Clitoral enlargement, ill‐developed labia majora, and fusion of the labioscrotal folds are features of the external genital appearance. Genetic mutations, including those of the SRY gene, have been reported [39]. It is sometimes referred to as Swyer syndrome, and one of the most important aspects of this condition is the increased incidence of gonadal neoplasms. Bilateral gonadectomy is therefore indicated as a prophylactic measure. Early sex hormone therapy is needed for normal puberty and bone mineral accumulation [40].
Ovotesticular disorder
Ovotesticular disorder denotes the presence of both ovarian and testicular tissue in the same patient. There may be an ovary on one side and a testis on the other or, more commonly, ovotestes situated bilaterally or unilaterally. The differentiation of the genital tract, the appearance of the external genitalia, and the development of secondary sexual characteristics are all variable. This depends on relative gene expression and hormone secretion, and histology of the gonads can include a mixture of ovarian and testicular tissue. The external genitalia are often ambiguous, but a uterus is almost invariably present, and 60% of patients have a 46,XX karyotype. Pregnancy is possible [41].
Structural developmental defects
Vagina
Vaginal agenesis (Müllerian agenesis)
The Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is the commonest form of Müllerian agenesis, occurring in about 1 in 4500 newborn females. The uterus, cervix, and upper vagina are absent in otherwise phenotypically normal 46,XX females. It presents at puberty when amenorrhoea is investigated. The vulva appears normal, but a short, blind‐ending vagina is found. MRKH type 1 affects only the upper reproductive tract, but type 2 is associated with renal (40‐60%), skeletal and, rarely, cardiac and hearing abnormalities [42,43]. Most cases appear to be sporadic but familial cases are described, and various associated genetic abnormalities have been studied [44,45].
Management of these patients requires a specialist multidisciplinary approach with expert psychological counselling and management advice [46]. The long‐standing technique described by Frank [47] of regular dilatation can create a neovagina in 95% of cases [48]. Several surgical techniques for vaginoplasty have been used with varying success, but sexual satisfaction is better with a non‐surgical approach.
Vaginal atresia
If the urogenital sinus fails to form the inferior portion of the vagina, then the lower vagina is replaced by fibrous tissue, and there can be an overlap with transverse vaginal septa. Most patients present at puberty with amenorrhoea. Associated anomalies of the cervix and uterus can exist [49,50], and surgical correction must be done on an individual basis by specialist teams [51]. A loss of function mutation of the TBX6 gene was found in one patient with distal vaginal atresia [52].
A degree of vaginal atresia can be part of complex anomalies including MRKH, Bardet–Biedl syndrome, McKusick‐Kaufman syndrome, Fraser syndrome [53], and Winter syndrome [54]. There is important overlap between Bardet–Biedl and McKusick‐Kaufman syndromes, and they cannot be reliably diagnosed at birth as the ophthalmic complications of Bardet–Biedl may manifest later [55].
Vaginal septa
Septa may be transverse or longitudinal. Transverse vaginal septa are generally located at the junction of the upper third and lower two‐thirds of the vagina. They are probably caused by failure of either the Müllerian duct or urogenital sinus contributions to the vagina to cavitate completely so they can occur at any level. It is inherited as an autosomal recessive trait in the Amish community [56]. Presentation is usually at puberty with retained menstrual products or a continuous vaginal discharge [57].
