Non-hormonal DSD

Abstract

Numerous congenital malformations result from defects of the anterior abdominal wall, genital region and perineum, but the hormone function in the foetus is normal. The key to recognition of these anomalies is that the anatomy is outside the line between male and female, as there are abnormalities of other structures. The more frequent malformations are described briefly in this chapter.

9.1 Introduction

Variations of genital development that lead to DSD are usually secondary to altered gonadal or hormonal function, but there is also a large group of congenital malformations affecting the abdominal wall and perineum that may lead to genital variants. Two groups are distinguished here: those with a defect in the morphogenesis of the genital tract alone and those with a more widespread abdominal or perineal defect, affecting the genitalia as well (Table 9.1) (Stephens et al. 2002).

Table 9.1 Classification of non-hormonal DSD

The key to recognition of these variants is that the external anatomy is outside the range between male and female. In particular, there is an anatomical defect that is beyond the effects of androgens acting on the genital tubercle and genital folds. By contrast, in hormonal causes of DSD, the morphological development is otherwise normal, and the dysmorphology is merely a consequence of abnormal androgenic or anti-Müllerian hormone (AMH) function.

9.2 Internal Genitalia

The commonest anomaly of the internal genital development is failure of normal fusion of the Müllerian ducts, leading to various degrees of uterine and vaginal separation. There may be a completely duplicated genital tract through to a partial bicornuate uterus or arcuate uterus. Whilst simple inspection of the introitus may occasionally identify an apparent duplication of the vagina, this does not necessarily represent complete Müllerian duplication. Thus, most variations in development of the female genitalia are only documented at endoscopy or laparoscopy, or on imaging studies (Fig. 9.1). A new classification system for Müllerian anomalies has been developed that enables careful complete classification of these anomalies (Grimbizis et al. 2013).

Fig. 9.1

Schematic diagrams of variations in fusion of the paired Müllerian ducts and types of atresia (Reproduced with permission from Stephens et al. (2002))

Complete or partial duplication in the urogenital ridge is well described, and this may present clinically as an extra testis.

Agenesis of the female genital tract has important implications for the woman in both function and psychological development (Box 9.1). One of the key causes for Müllerian duct agenesis is a primary anomaly in the mesonephros and its duct, the mesonephric or Wolffian duct. The latter is an intrinsic organiser of Müllerian development, as the Müllerian ducts use the Wolffian ducts to guide their migration to the cloaca between 6 and 8 weeks of gestation. The elongating solid tips of the Müllerian ducts grow along the basement membrane of the adjacent Wolffian ducts. Failure of the Wolffian duct to reach the cloaca by 4 weeks of gestation may prevent the ureter budding from the lower Wolffian duct (leading to ipsilateral renal agenesis) as well as distal agenesis of the Müllerian duct (Rokitansky sequence). This is the classic Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome type II (Stephens et al. 2002). When such a change occurs later, for example, between 8 and 12 weeks of development, the vagina may fail to canalise, leading to atresia, but the urinary tract is not affected, thereby leading to MRKH syndrome type 1 (Table 9.2).

Table 9.2 Timing of events in urogenital tract

Box 9.1 Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome

MRKH syndrome (OMIM 277000) with agenesis of part or whole of the female genital tract is present in about 1/4500 females. It can be classified into two subgroups: with or without associated anomalies.

MRKHS Type I (OMIM 277000): Isolated Müllerian duct agenesis with absent uterus and vagina.

MRKHS Type II (OMIM 601076): Müllerian duct agenesis with associated anomalies of the urogenital ridge (Wolffian duct development, ureteric bud development, renal dysplasia) and cervical somites (also called MURCS association. Müllerian duct agenesis, Renal anomalies, Cervical Somite anomalies). This may also be called Genital Renal Ear Syndrome (GRES; OMIM 267400) when there are anomalies of the middle ear, with associated deafness (Morcel et al. 2007; Bernardini et al. 2009).

9.3 External Genitalia

Isolated variations of the external genitalia may be readily confused with hormonal causes of DSD, but the overriding feature is that the altered anatomy cannot be explained by atypical hormonal effects. Failure of the genital folds to form around the cloacal membrane is a sign of an early anomaly of fundamental embryogenesis and hence is relatively uncommon in surviving babies. Such anomalies include ectopia of the outer genital fold, leading to ectopic hemi-scrotum or labium majorum (Fig. 9.2), although these differences may be caused by pressure from the heel of the foetus. More fundamental nonhormonal DSD may include complete absence of the genital tubercle, which causes penile agenesis in boys. In this rare anomaly, the urethra usually opens via a meatus located within the anterior tip of the anal canal, if present. An important clue to the prognosis is the presence of a median raphe in the scrotum: when this is absent, there is a very high likelihood of renal dysplasia or agenesis (Fig. 9.3) (Srinivasan et al. 2003).

Fig. 9.2

Ectopic labium majorum, secondary to failure of the outer genital fold to develop around the cloacal membrane, in a baby with a recto-vestibular fistula

Fig. 9.3

Penile agenesis, showing empty scrotum, which has no median raphe. The baby had cystic dysplasia of ectopic pelvic kidneys (Reproduced from Srinivasan et al. (2003); with permission of the publisher)

During the formation of the vaginal plate, if there is insufficient caudal elongation and migration to the vestibule, then the baby girl is born with a common opening for the urinary and genital tracts, known as a urogenital sinus. This is not related to androgenic suppression of vaginal plate development, as the vagina is otherwise well formed; the variation lies in the genetic regulation of migration of Müllerian tubercle and vaginal plate to the vestibule. Acquired adhesion of the labia minora is occasionally misdiagnosed as a congenital anomaly; however, this is not present at birth and develops as a result of mild inflammation of the atrophic labial surfaces and secondary labial adherence during healing. Labial adhesions are rarely noticed below 6 months of age and frequently present from 6 months up to 2–3 years (Leung et al. 1993), and evidence suggests they spontaneously resolve as they are almost never found in post-menarchal girls (Norris et al. 2018).

9.4 Lower Abdominal Wall Defects

The lower anterior abdominal wall is formed by the ectoderm during embryonic folding, as well as by migration of the lateral plate mesoderm around the developing trunk to form the muscles of the abdominal wall. Migration of mesodermal cells between the umbilical stalk and the immediately adjacent cloacal membrane leads to proliferation of muscle precursors that will form the abdominal wall musculature as well as contribute to the development of the anterior bladder wall. Failure of this mesenchymal expansion may lead to various defects in the lower anterior abdominal wall, from classic bladder exstrophy through to epispadias. The anatomy in classic bladder exstrophy, where the genital tubercle in males is often separated from the outer genital folds (that form the scrotum) by a bridge of skin, suggests that the mesenchyme may have migrated aberrantly between the genital tubercle and the outer genital folds, disrupting the urethral development and leaving a deficiency in the abdominal wall above the genital tubercle (Fig. 9.4a).

Fig. 9.4

(a) Classic bladder exstrophy, with deficiency of the anterior abdominal wall and the anterior wall of the bladder and urethra. (b) Epispadias in a girl showing a bifid clitoris. (c) Epispadias in a boy showing the open urethral plate exposed on the dorsal surface of the penis

Epispadias is a less severe variant where confusion with other DSD is less likely, although in girls the clitoris may be bifid (Fig. 9.4b), while in boys the urethra and penis are atypical (Fig. 9.4c).

9.5 Perineal Anomalies

Perineal development includes not only the urogenital tracts, but also the hindgut, so that atypical development may affect all three tracts and their respective external openings (Holschneider and Hutson 2006). One characteristic anomaly in this category is an anorectal malformation with a cutaneous fistula in the male, which is usually within the median raphe. The anatomy in boys with a recto-bulbar urethral fistula is potentially ambiguous, as the anomalous connection between the terminal hindgut and the bulb or anterior urethra is often associated with non-fusion of the hemi-scrotal folds, producing a bifid scrotum (Fig. 9.5a).

Fig. 9.5

(a) Anorectal malformation in a boy with a recto-bulbar fistula. The bifid scrotum is quite characteristic of this variation. (b) Anorectal malformation in a girl with a vestibular fistula distorting the genital anatomy

In females with anorectal malformations, the fistula is most commonly in the vestibule, leading to variable degrees of dysmorphogenesis of the introitus. The absence of an obvious anal opening, however, is a clear sign of a non-hormonal anomaly of embryogenesis (Fig. 9.5b).

In some foetuses, the genital variation is secondary to compression of the foetus in utero, with pressure atrophy of variable genital and perineal structures. An example of this is a baby presenting with chordee of the penis associated with not only less ventral growth of the penile shaft but also an atypical urogenital opening, hypoplastic hemi-scrotum with an ipsilateral absent testis. Although this child could be mistaken to have mixed gonadal dysgenesis or ovotesticular DSD, careful inspection of the external genitalia demonstrates features that are not consistent with a urogenital sinus or hormonal DSD. Extrinsic pressure from the heel of the child onto the perineum may cause this anomaly with additional clues being the urethral meatus at the tip of the glans, an opening on the ventral surface which may look like a pressure sore or a urethral fistula after hypospadias repair, and careful palpation may reveal an atrophic nubbin in the hemi-scrotum consistent with ischaemic atrophy of the testis. Examination under anaesthesia may show that the heel of the child fits perfectly into the perineum (even at 6 years of age!) (Fig. 9.6). Extrinsic compression of the embryo or foetus is well described by Stephens and is discussed in detail in (Stephens et al. 2002).

Fig. 9.6

Pressure sore over the urethra in a boy causing an atypical urethral opening initially thought to be a urogenital sinus. The boy had secondary chordee caused by scarring from the ischaemic necrosis of the urethra, as well as atrophy of the left testis. The right heel could be folded to fit perfectly into the perineum over the atypical urethral opening

9.6 Cloacal Maldevelopment

The cloaca is the endodermally derived common cavity for the anorectum and urogenital tracts. Failure of development of the posterior portion of the cloaca along with incomplete separation of the urogenital tracts may lead to persistence of the primitive cloacal cavity at birth. In female infants, this means all three tracts—urinary, genital and gastrointestinal—exit through a common opening. This anomaly may distort the external genital development and lead to ambiguity in appearance. This is particularly the case if the external opening is very small so that the genital folds appear fused, secondary to atypical early development, rather than androgen-induced fusion. The cloacal opening may be so small that it causes urinary obstruction with enlargement of the clitoral hood in a manner similar to distal urinary obstruction in a boy with phimosis. On physical examination, however, the erectile tissue is not enlarged; only the skin is stretched by the urinary blockage to create a phallus-like structure.

The key to recognition of this non-hormonal DSD is the very short introitus or pin-hole opening in the genital folds in a baby with an absent anus (McMullin and Hutson 1991) (Fig. 9.7a).

Fig. 9.7

(a) Cloacal anomaly with a tiny opening in the genital folds associated with overgrowth and stretching of the clitoral foreskin secondary to urinary obstruction. This has led to significant distortion of the external genitalia. (b) Cloacal exstrophy in a baby showing the exposed bowel mucosa centrally and bladder mucosa laterally. The partially concealed external genitalia are widely separated

Arrested development at the cloacal stage in association with abnormal mesodermal development in the lower abdominal wall causes the rare cloacal exstrophy. This is associated with an unfused pelvic ring and exposure of the dysplastic midgut or hindgut on the surface between the bladder mucosal plate on each side. The genitalia are distorted and widely separated into two halves (Fig. 9.7b). Not unexpectedly, there are frequently multiple other developmental variations in the baby, which may impact on the plan of management. The obvious involvement of all the pelvic organs and the abdominal wall means that these infants are easily distinguished from hormonal DSD.

There are two other rare conditions of the pelvis and perineum that lead to atypical external genitalia. The first of these is so-called “caudal regression”, where regulatory signals controlling growth of the lower half of the embryo are deranged. The most severe variant of this is sirenomelia, where the legs are fused like a mermaid. In this well-described but extremely rare condition, the umbilical artery is a single vessel given off by the mid-abdominal aorta, which inhibits all distal growth by “vascular steal”. In one such case that we have seen, the pelvic organs were absent, apart from the gonads, which were supported by ovarian arteries arising from the upper aorta above the abnormal umbilical artery. The anus was absent, the genital folds were rudimentary, and the urinary tract drained via a single dysplastic ureter directly onto the perineum (Fig. 9.8) (Stanton et al. 2003).

Fig. 9.8

Severe caudal regression in the rare anomaly of sirenomelia, leading to atypical external genital development (Reproduced with permission from Stanton et al. (2003))

The final, rare anomaly of the external genitalia is caused by partial duplication of the caudal embryo, which is a form of incomplete conjoined twinning. There is little confusion with more common DSD, and management involves either removal of one half of the organs or joining the duplicated structures together, depending on the precise anatomy.