sexual development is dependent on several activating, repressing, and genetic factors. Disorders of sexual development (DSDs) include a range of conditions that can affect the internal and external genital [21]. They may be recognised at birth as the phenotypical appearance may not be characteristic of either male or female. However, the problem can also present at a later stage with an increasing virilised appearance of the genitalia, delayed or absent puberty, or infertility. These patients must be managed in specialist centres by a multidisciplinary team for discussion of management and the timing of any surgical intervention [22]. There are ethical issues and patient opinion to be taken into account, and there are guidelines for referral to specialist paediatric endocrinology services for advice and management [23].
The classification of DSDs has been revised [24], and Table 1.2 shows the currently accepted method of categorising these conditions. Terms such as intersex and hermaphrodite are no longer acceptable.
Sex Chromosome DSD
Turner’s syndrome
Turner’s syndrome is reported to occur in 1 in 2500 live female births [25]. There is complete or partial absence of the sex chromosome – most have the karyotype 45,XO, but 15% have a 46,XX mosaic pattern, and 7–10% have some Y chromatin present. The ovaries, located in their normal anatomical positions, consist mainly of fibrous stroma and are termed streak gonads. Germ cells rarely survive meiosis, follicular formation usually fails, and the resulting streak gonads are sterile and devoid of endocrine activity. At birth the genital ducts and external genitalia are entirely female, although clitoral enlargement may occasionally be present. However, almost 25% of girls with Turner’s syndrome show some secondary sexual development, 2–5% menstruate due to some residual ovarian function, and rarely, can have spontaneous pregnancies [26], although these are high risk because of the associated cardiac complications. Patients with Turner’s syndrome are of short stature and exhibit a range of somatic abnormalities including webbing of the neck, coarctation of the aorta, and renal anomalies. There is also a predisposition to develop diabetes mellitus and other autoimmune diseases, particularly those affecting the thyroid [27]. Hormonal treatments are required, and these patients need multidisciplinary specialist management throughout life [28]. There is a reduced incidence of breast cancer, but increased risk of gonadoblastoma and endometrial cancers [29].
Table 1.2 Classification of disorders of sexual development (DSDs).
| 1. Sex chromosome DSD |
| Turner syndrome (45,X) Klinefelter syndrome (47,XXY) Mosaicism 45,X/46,XY Triple XXX syndrome XXYY syndrome |
| 2. 46,XX DSD |
| Androgen induced/androgen excessCongenital adrenal hyperplasia (CAH)Placental aromatase deficiencyGlucocorticoid receptor mutationMaternal androgen secreting tumours (e.g. luteomas)Androgenic drug exposure OthersSyndromic associations, e.g. cloacal dystrophiesMüllerian agenesisVaginal atresiaUterine anomalies |
| 3. 46,XY DSD |
| Disorders of androgen synthesis and actionLH receptor mutationsSmith–Lemli–Opitz syndromeCholesterol side chain cleavageSteroid protein mutations5∝‐reductase deficiencyAndrogen insensitivity syndromeLeydig cell agenesis OthersSyndromic association of male genital development, e.g. hand‐foot‐genital, cloacal dystrophiesPersistent Müllerian duct syndromeCryptorchidismCongenital hypogonadotropic hypogonadism |
| 4. Disorders of gonadal developmentComplete or partial gonadal dysgenesisOvotesticular DSD |
Mosaicism
45,X/46,XX mosaicism and X chromosome abnormality
This form of mosaicism is the most common cause of ovarian dysgenesis after Turner’s syndrome. One gonad may be of the streak type and the contralateral gonad a normal or hypoplastic ovary; alternatively, both ovaries may be either normal or hypoplastic. There are fewer of the somatic abnormalities associated with Turner’s syndrome, the phenotype is invariably female, and some will menstruate and even be fertile.
45,X/46,XY MOSAICISM AND Y CHROMOSOME ABNORMALITY
A highly diverse phenotype is encountered in 45,X/46,XY mosaicism since the presence of a Y‐bearing cell line may induce some testicular differentiation. Such individuals may appear typically male or female or may possess ambiguous external genitalia with varied genital duct development. The prevalence of gonadal tumours in these patients can vary with phenotype and appears to be higher in those with a female phenotype [30].
46,XX DSD
The chromosomal makeup is 46,XX with the ovaries and Müllerian duct derivatives as normal. The external genitalia are abnormal. The clitoris is enlarged, variable degrees of labial fusion are seen, and the urethral opening may not be distinct from the vagina. The external genitalia of the male foetus are completely masculinised by 84–98 days. If a female foetus is exposed to significant androgen levels, in the presence of 5∝‐reductase, before the end of this period of development, complete virilisation will occur. Lower levels or later exposure will produce various forms of incomplete virilisation. The source of the androgen excess may be foetal, maternal, or exogenous.
Foetal androgen excess
Foetal androgen excess is generally due to forms of CAH. The most common disorder in this group is virilising CAH. This is usually an autosomal recessive inherited condition due to mutations in the CYP21A2 gene, leading to reduced 21‐hydroxylase activity. This in turn causes reduced levels of cortisol and aldosterone, a rise in ACTH, adrenal hyperplasia, and consequently high levels of 17‐hydroxyprogesterone and testosterone. As salt wasting and adrenal insufficiency in the neonatal period are serious complications, screening programmes are in place, and most cases are diagnosed in this period.
Typical CAH results in clitoromegaly, fusion of the labia majora, and a single perineal opening dividing proximally into the urethra and vagina. Expert surgery is required, but the timing of this can be difficult. The aim of surgical intervention is to bring the vagina to normal position on the perineum, to separate the distal vagina from the urethra, and to ensure an adequate vaginal introitus [31]. It is important to preserve clitoral innervation if clitoromegaly is to be reduced surgically. However, clitoromegaly can improve with time, so surgery for this can be delayed. The main complications of these procedures are incontinence and enuresis, wound breakdown, infection, and vaginal stenosis [32]. With follow‐up, most patients are sexually active but report reduced sensation.
Atypical presentations may not be diagnosed until adolescence or adulthood, and features can overlap with those of polycystic ovarian syndrome. Patients with CAH are at increased risk of diabetes, thromboembolic disease, and thyroid disorders [33].
There are other autosomal recessive forms of CAH giving rise to disorders of steroidogenesis. These include deficiencies of 11‐ß‐hydroxylase deficiency (CYP11B1 mutation), 3‐ ß‐hydroxysteroid dehydrogenase (HSD3B2 mutation), P450 oxidoreductase (POR mutation), aromatase (CYP19A1 mutation), and 17‐hydroxysteroid dehydrogenase. Deficiencies of 3‐ ß‐hydroxysteroid dehydrogenase and 17‐hydroxysteroid dehydrogenase
