Complete gonadal dysgenesis – Swyer syndrome

Swyer syndrome was first described by Swyer in 1955 and was identified as yet a new form of ‘hermaphroditism’, where, unlike the more common forms, a uterus and vagina were present. The condition is now thought to be caused by a mutation of the SRY gene as seen in 10% of cases or a defect in a different TDF, such as the SF-1 gene.

The gonads remain dysgenetic and thus produce no hormones in utero , postnatally or in puberty. As a consequence, there is no virilisation and the genitalia are unambiguously female at birth. The lack of secretion of AMH results in the normal development of the uterus, fallopian tubes and vagina. The affected person typically presents in adolescence because of primary amenorrhoea, associated with delayed puberty. The stature is tall and the uterus – although present – may not be identified at initial assessment as it has not been stimulated by oestrogen production. The mutation leading to the disorder is usually sporadic, although certain familial cases have been described and, therefore, sisters of affected individuals should be screened for the condition. Making the diagnosis as early as possible is crucial, as the gonads have an increased risk of becoming malignant. This can be as high as 40% and occur in childhood or early adolescence, even before the condition is suspected.

Management consists of induction of puberty with oestrogen administration, and after withdrawal bleeding has occurred, administration of a combined hormonal preparation containing oestrogen and progesterone.

The uterus has the potential to develop and grow and pregnancy is possible through egg donation. Gonadectomy should be performed as soon as the diagnosis is made, and this can be performed laparoscopically. Salpingectomy is usually performed at the same time, as it is important to remove the gonads with a wide margin to remove the risk of malignancy. This may, in fact, improve fertility rates, as the operated adnexum can develop adhesions and this can lead to the formation of hydrosalpinges, which can reduce the success of assisted reproduction.

Gonadal dysgenesis associated with Wilms tumour suppressor gene mutations (Denys–Drash syndrome and Frasier syndrome)

The Wilms tumour suppressor gene (WT1) plays an important role in renal and genital development and its mutations lead to renal disease, ranging from early-onset nephropathy and nephroblastoma to gonadal dysgenesis in XY individuals. Patients with Denys–Drash syndrome typically present with early onset nephrotic syndrome and hypertension, secondary to glomerular diffuse mesangial sclerosis resistant to treatment. Patients with a 46XY karyotype have ambiguous genitalia and abnormally developed testes, whereas in a 46XX karyotype, ovaries develop normally and allow for normal pubertal development. The conditions quickly progresses to end-stage renal failure, at which time it is usually recommended that the kidneys are removed, because there is an increased risk of developing Wilms tumour, a form of nephroblastoma.

Frasier syndrome is caused by mutations in intron 9 of the WT1 gene. Unlike the Denys–Drash syndrome, there does not seem to be an increased risk of Wilms tumour and the progression of renal failure is slower and occurs later in life. Patients usually present in mid- to late childhood with focal segmental glomerular sclerosis (FSGS), leading to nephrotic syndrome. XY individuals have an unambiguously female phenotype with normal mullerian structures. The gonads are, however, streak and the condition is usually identified because of primary amenorrhoea and delayed puberty.

As with the Swyer syndrome, bilateral gonadectomy should be performed as soon as the diagnosis has been made, because of the risk of gonadal malignancy.

Mixed or Partial Gonadal Dysgenesis

This is a form of DSD where the gonads are dysgenetic but testicular determination has occurred to a certain extent. Such cases present with ambiguous genitalia and a mixture of Woolfian and mullerian intra-abdominal structures. This condition can be associated with a 45X0/46XY mosaicism present only in the gonad, which may not be detectable through peripheral karyotyping. The gonads can be streak, although testicular tissue can be identified, often on the side where mullerian regression and woolfian tube development has occurred. Cases of mixed gonadal dysgenesis typically present at birth because of ambiguous genitalia. It is essential that the gonads are removed, as there is a potential for malignancy in all dysgenetic gonads.

Vanishing testes syndrome or testicular regression syndrome (TRS)

In this condition, gonadal tissue is not identified, either because of non-formation, or because of in utero regression or destruction. It is thought to be a rare condition with a wide spectrum of phenotypes, depending on the timing of testicular regression, ranging from clear female phenotype, ambiguous genitalia or male genitalia with absent testes. In most cases, the cause for testicular regression is thought to be secondary to torsion during testicular descent, leading to ischaemic necrosis of the gonadal tissue.

Congenital lipoid adrenal hyperplasia

This is due to a defect in the conversion of cholesterol to pregnenolone, the first step in steroid production both in the adrenal glands and the gonads. The condition is caused by a mutation in the steroidogenic acute regulatory protein (StAR protein), which is responsible for the transfer of cholesterol within the mitochondria.

In early congenital lipoid adrenal hyperplasia, there is some degree of steroidogenesis, as a proportion of cholesterol is transported independently to the StAR protein. However, as increased adrenocorticotrophic hormone (ACTH) is produced to stimulate steroidogenesis, more cholesterol accumulates within the cell in lipid droplets, which, in turn, damage the cellular structure and function, further diminishing steroid production.

In XY individuals, the process of lipoid degeneration also occurs within the testes, as their stimulation begins in utero . This leads to destruction of the testicular structure and because no androgens are produced, the newborn is phenotypically female.

In XX individuals, the ovaries remain unaffected until puberty, because of the lack of stimulation. Although pubertal development occurs and withdrawal bleeding is possible, cycles are usually anovulatory.

5a- reductase deficiency

This condition is found in patients born with female or mildly ambiguous genitalia, who then go on to become severely virilised at puberty, which can lead, in some cases, to a change in gender. Larger numbers of individuals with 5a reductase deficiency were identified in the Dominical Republic, where the condition was known as ‘guevedoce’ meaning penis at 12 in the local dialect. Investigation in these patients led to the identification of the defect in the enzyme 5a reductase, which is necessary for the reduction of testosterone to the more potent androgen dihydrotestosterone. The defect is transmitted in an autosomal recessive somatic fashion and therefore is more common in consanguineous families.

The anatomical features vary, although typically the phallus is small and the urethral opening is on the perineum. The vagina can be absent or with its opening not obviously visible, or it can be present, but short and blind ending. The testes are thought to always be extra-abdominal, lying in the inguinal canal, labia majora or scrotum. Spermatogenesis is impaired, possibly secondary to the hormonal defect or to the incomplete descent of the testes. Diagnosis is based on the clinical findings and is confirmed biochemically with an increased testosterone-to-dihydrotestosterone ratio.

In patients where the sex of rearing is female, the gonads are removed early, to prevent virilisation, which can be profound in puberty. Depending on the degree of virilisation, feminising surgery may be considered to reduce the size of the clitoris and lengthen the vagina.

Timing of genital surgery is an issue of great debate. Until recently, the accepted practice was to perform feminising genitoplasty in infancy, as this was thought to reinforce gender identity. However, it is now becoming clearer that clitoral surgery affects its sensitivity. Furthermore, surgery performed in childhood is likely to require revisions in adolescence. With this in mind, the tendency is nowadays for avoiding surgery in cases of mild clitoromegaly. Parents should be informed of the risks of surgery with regard to sensitivity of genital structures and future sexual function.

If a vaginoplasty is required, this should be performed in late adolescence to early adulthood. The preferred procedure for women with no vaginal dimple is the laparoscopic Davydov procedure, where the space between bladder and rectum is dissected and lined with peritoneum.

17b ketosteroid hydroxylase deficiency

The enzyme 17b ketosteroid hydroxylase is necessary for the conversion of androstenedione to testosterone. The condition is caused by a mutation in an autosomal recessive gene and the condition, as in 5a-reductase deficiency, is more common in consanguineous families.

It is thought to be a rare condition, although it is more commonly seen in populations with significant geographical isolation or increased consanguinity.

The phenotype varies, although virilisation is less prominent when compared to 5a-reductase deficiency and thus, the majority of patients are reared as females and identified at puberty because of virilisation. The diagnosis can be made earlier if an older affected sibling is diagnosed or if the gonads are palpable within the inguinal region. Early diagnosis allows for earlier gonadectomy to prevent non-reversible virilisation at puberty (e.g., clitoromegaly, male body habitus and deepening of the voice).

Diagnosis is supported biochemically by a reduced testosterone-to-androestenedione ratio, especially after stimulation with human chorionic gonadotropin (hCG) and is confirmed with mutational analysis of the enzyme.

Complete androgen insensitivity syndrome (CAIS)

This is the most common of conditions leading to the presentation of an XY female with an estimated incidence of 1 in 40000–60000 births. The condition most commonly becomes identified in adolescence because of primary amenorrhoea, in association with normal breast development and scanty pubic and axillary hair growth. The external genitalia are unambiguously female. However, the vagina is blind ending of variable length and the uterus is absent. This is because testes produce AMH in normal amounts in utero , and this leads to the regression of mullerian structures, including the upper third of the vagina.

The syndrome was first described by Morris in 1953 and was initially called ‘testicular feminisation syndrome’, a name that has subsequently been rejected as both derogatory and incorrect in its description. Testes in women with complete androgen insensitivity syndrome (CAIS) show many similarities with those seen in cryptorchidism, suggesting that anomalies in CAIS testes depend on abnormal testicular position rather than androgen resistance. This is further supported by the fact that germ cells numbers are normal in testes removed at less than 1 year. Testes are normally developed and can lie anywhere within their line of descent. They can often be located within the inguinal canal and this can lead to the formation of an inguinal hernia. In a retrospective review of 120 cases of CAIS, more than half had presented in childhood with a unilateral or bilateral inguinal hernias. In approximately one-third of cases, the gonads were palpable within the inguinal canal. This has led to the conclusion that female infants with bilateral inguinal hernias should be screened for CAIS or another XY DSD.

The cause for CAIS is a defect in the androgen receptor (AR), a nuclear receptor that mediates the action of all androgens. In CAIS, as the name implies, there is complete absence of receptor activity, whereas, in partial androgen insensitivity syndrome (PAIS), activity can be variable, leading to a wide spectrum of phenotypes. The gene encoding for the AR is located in the long arm of the X chromosome and the condition is therefore X linked.

There is a small risk of seminoma; however, this appears to be low, in the range of 3–5%, similar to cryptorchidism, and does not warrant removal of testes prior to puberty, as few cases of malignancy have been described in adolescence.

Leaving testes in situ until after puberty allows for breast development to happen naturally without the need for puberty induction with exogenous administration of oestrogen. It also permits for the patient herself to make an informed decision about the timing of surgical procedure.

After gonadectomy has been performed, women with CAIS need to remain on long-term oestrogen replacement, mainly to protect bone mineral density. Nevertheless, it has been shown that women with CAIS fare less well in terms of risks of osteopenia and osteoporosis, when compared with other XY females, possibly because of the role of androgens in cortical bone mineralisation. It is, therefore, crucial, that women with CAIS remain under regular review with bone mineral density scans, to adjust the dosage of oestrogen or add other medication to prevent or treat osteoporosis.

Women with CAIS have a female gender identity and in the vast majority have a female heterosexual orientation. The perceived impression is that they have a potential for normal sexual satisfaction; however when this was objectively assessed with standardised questionnaires, sexual function was shown to be deficient, mainly due to psychological maladaptation to having a DSD and vaginal penetration difficulties due to vaginal hyoplasia.

Vaginal hypoplasia can be effectively managed with vaginal dilation, provided this is accompanied by adequate psychological support in a multidisciplinary team setting. Vaginal dilation, also known as the Frank method, consists of inserting vaginal moulds of gradually increasing sizes and applying pressure to the existing vaginal dimple. Completion of treatment is usually achieved in 3–5 months and is effective in approximately 80% of cases.

Where vaginal dilation has not been effective, vaginal elongation can be achieved with the laparoscopic Vecchietti method.

Partial androgen insensitivity syndrome (PAIS)

If the androgen receptor retains some activity, incomplete virilisation occurs. This leads to a wide spectrum of phenotypes, ranging from subtle virilisation, such as mild clitoromegaly to subtle undermasculinisation, such as hypospadias or microphallus. Thus, children with PAIS can be assigned either male or female, depending on the degree of virilisation. This variation depends on the type of mutation leading to androgen insensitivity, but can also be seen in patients with the same mutation, sometimes even within the same family. This can be caused by somatic mosaicism, where virilisation is mediated through the normally functioning wild-type androgen receptor, or it can be caused by differences in 5a DHT availability within the genital fibroblasts.

Where the sex of rearing has been decided as female, it is important to remove the gonads early, to prevent further virilisation. Surgery may also be required to reduce the size of the clitoris and create a vagina. The same principles apply similar to those mentioned in patients with 5a reductase deficiency.

Leydig cell dysfunction

This is due to a defect in the luteinising hormone (LH) receptor (LHR). The gonad initially develops normally into testicular tissue; however, because hCG needs the LHR to stimulate Leydig cells, no testosterone is produced and Leydig cells remain atrophic. Testes produce AMH normally and this leads to the regression of mullerian structures. LHR inactivity leads to a variety of phenotypes, ranging from a female adolescent that presents because of primary amenorrhoea to a child with genital ambiguity. Diagnosis is confirmed on histology of the gonad, which shows absence of Leydig cells.