female foetus, the urogenital sinus remains open as caudal growth of the vaginal plate brings the urethral and vaginal openings into this region, converting it into the vestibule."/>
Figure 1.12 (a) The genital and anal membranes rupture. (b) In the female foetus, the urogenital sinus remains open as caudal growth of the vaginal plate brings the urethral and vaginal openings into this region, converting it into the vestibule.
Development of the epithelia
The epidermis of the vulval skin and its appendages – hair, sebaceous and sweat glands – develop from the ectoderm with the dermis developing from the mesoderm. The primitive epidermis is established about the eighth day when the ectoderm differentiates within the developing embryo. At this stage, the epidermis is a single layer of cells, but then a second outer layer develops, the periderm, beneath which the primitive epidermis begins the process of stratification. Keratinisation occurs at the end of the sixth month, and the periderm is sloughed into the amniotic fluid. Cells that are shed from the stratum corneum combine with sebaceous secretions to form the vernix, which makes the embryo impervious to the amniotic fluid and persists until birth.
Three cell types invade the developing epidermis during the first 6 months of intrauterine life. Melanocytes, derived from neural crests, and Langerhans cells, derived from the mesoderm, are present at the end of the third month, while Merkel cells, the origin of which is uncertain, are present by the sixth month [14,15].
The dermo–epidermal junction is flat in all parts of the body until hair and glandular primordia reach the dermis. Primary vellus hair follicles begin to form during the third month of gestation, and the process proceeds in a cephalocaudal manner. Secondary follicles form in close association with the primary follicles, and it is thought that the full complement of hair follicles is present at birth.
Sebaceous glands arise as buds mostly from the hair follicles. They begin to appear during the fourth month and rapidly differentiate into sebum‐producing cells. The development and function of sebaceous glands before birth and in the neonatal period is thought to be regulated by maternal androgens and endogenous foetal steroids. At birth, the glands are large and well developed over the entire body and display the same regional variation in size as is seen in the adult. Postnatally they involute and remain quiescent until puberty.
Eccrine sweat glands start to appear during the third month of prenatal life, and their ducts are open to the skin surface by the sixth month. The premature infant usually shows an absent or limited sweating response [16], even though the glands are innervated as soon as they develop. The number of sweat glands, like hair follicles, seems to be complete at birth.
Apocrine development occurs at sixth months of intrauterine life, and it has been suggested that their primordia develop in association with each hair follicle but then regress in all areas except the areola, axilla, scalp, eyelids, external auditory meatus, umbilicus, and anogenital region [17]. The glandular activity begins during the last trimester, but ceases soon after birth – but then begins again at puberty.
The dermis originates from the mesoderm in the second month of embryonic life. The mesodermal cells form fibroblasts, macrophages, melanoblasts, and mast cells with the matrix composed of collagen and elastin. The organisation of the dermis is progressive throughout gestation and is not complete until some months after birth.
There has been debate about the origin of the vaginal epithelium, but more recent molecular studies, including those of PAX2 and FOXa1 immunostaining [18,19], support a derivation from the urogenital sinus epithelium, as originally suggested [20].
Disorders of sexual development
Normal 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