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].
A longitudinal vaginal septum is not uncommon and lies in the sagittal plane. They are the result of a fusion defect in the Müllerian system and are associated with abnormalities of the uterus and cervix. In one study of 83 women with a longitudinal vaginal septum, only 3 had a normal uterine cavity [58]. These septae may be displaced to one side and difficult to see. Surgical removal is recommended as they can cause major difficulties with vaginal delivery. A double vagina may be found where one side is not patent, and menstrual products collect in one side causing obstruction.
Imperforate hymen
This is commonly caused by the failure of the central epithelial cells of the hymenal membrane to degenerate. It can also arise as the result of an inflammatory reaction in the hymen after birth, presenting with a build‐up of fluid behind the membrane (mucocolpos). This can lead to renal failure secondary to urethral obstruction [59].
Imperforate hymen does not usually present until puberty where a membrane, sometimes with a bluish tinge if thin, is seen at the distal end of the vagina and the hymen may be separate. Unusual variations include extension of the membrane into the vagina which can rarely obstruct one side if the vagina is septate.
Other rare hymenal abnormalities include a cribriform, microperforate, or septate hymen (see Chapter 51).
Vaginal cysts
In the neonatal period, vaginal cysts may be found in the anterior or lateral walls of the vagina at the introitus and usually rupture spontaneously. Occasionally one or more of these may enlarge and obstruct the urethra. They are thought to be inclusions from the urogenital sinus epithelium and may persist asymptomatically into adulthood [60]. Mucous cysts are found in the same location, interior to the labia minora and external to the hymen, in about 3% of adults attending a vulval clinic [61]. In addition, the Wolffian ducts, which degenerate in the female, leave caudal remnants in the lateral walls of the vagina. These remnants may undergo cystic degeneration, when they are termed Gartner’s cysts. If large, these can cause dyspareunia or urinary symptoms. Transvaginal ultrasound is helpful to confirm their presence, and surgical excision was reported as successful in a series of 29 patients [62].
External genitalia
Various abnormalities of the vulva are caused by disturbances of sexual differentiation, leading to an ambiguous appearance of the external genitalia. Other developmental defects, such as duplication, often occur in association with abnormalities of the upper reproductive tract and urinary system.
The clitoris may be absent [63], probably as a result of the genital tubercles remaining hypoplastic or failing to fuse. A penis‐like clitoris in 46,XX DSD is described which is likely to be due to abnormality in the development of the cloacal membrane [64]. Clitoral enlargement occurs in several genetic syndromes (see Chapter 51).
Agenesis of the labia minora and clitoris has been described in isolation [65]. Hypertrophy and/or marked asymmetry of the labia minora may occur without any underlying problem. True hypoplasia of the labia minora occurs infrequently and may be a sign of defective steroidogenesis. Fusion of the labia minora may occur in association with defective sexual differentiation and should not be confused with the superficial labial adhesions seen in the neonatal period or in infancy as a result of an inflammatory condition.
Vulval and urinary system abnormalities
Kidney
Bilateral renal agenesis is a lethal congenital malformation and in the female is frequently associated with anomalies of the external genitalia, absence of the uterus and vagina, and abnormalities of other systems [66]. Unilateral renal agenesis may be associated with malformations of the external genitalia in up to 40% of cases [67].
Ureter
The ureteric bud arises from the Wolffian (mesonephric) duct and separates off when the duct is incorporated into the urogenital sinus to form the trigone of the bladder and urethra. Failure of dissociation between the ureteric bud and the Wolffian duct in the female will allow the ureteric orifice to be located at any site along the caudal remnant of the Wolffian duct (Gartner’s duct). Secondary rupture of Gartner’s duct into the vagina [68] allows for vaginal drainage of urine from the ectopic ureter. The most common site for the vaginal opening of an ectopic ureter is the vestibule and usually presents as continuous