Disorders of sexual development and abnormal genital tract development

Question 1

Human sex development - components (3)

Answer 1

1. Chromosomal sex = presence of X and/or Y chromosomes
2. Gonadal sex = development of the gonad into either testis or ovary
3. Phenotypic or anatomic sex = appearance of internal and external genitalia

Note: sex development differs from the concept of gender

Question 2

Disorders of sex development (DSD) - classification (3)

Answer 2

DSD = congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical

1. 46XX karyotype (4)
   i. Virilizing forms of congenital adrenal hyperplasia (CAH)
   ii. Ovo-testicular DSD (previously termed true hermaphroditism)
   iii. Maternal virilizing condition or ingested drugs
   iv. Placental aromatase deficiency (?)
2. 46XY karyotype (5)
   i. Androgen insensitivity syndrome (AIS)
   ii. Defects of testosterone biosynthesis (e.g. 5 α -reductase deficiency,
   17 β -hydroxysteroid dehydrogenase deficiency).
   iii. Swyer syndrome (pure gonadal dysgenesis)
   iv. Partial gonadal dysgenesis 2° to single gene mutations
   v. Leydig cell hypoplasia
3. Sex chromosome DSD (3)
   i. 47XXY Klinefelter syndrome (and variants)
   ii. 45X0 Turner syndrome (and variants)
   iii. Chromosomal mosaicism (e.g. 45X/46XY, 46XX/46XY chimerism)

Question 3

Sex chromosome DSD - types

Answer 3

1. 47XXY Klinefelter syndrome (and variants)
2. 45X0 Turner syndrome (and variants)
3. Chromosomal mosaicism (e.g. 45X/46XY, 46XX/46XY chimerism)

Question 4

Klinefelter syndrome - phenotype

Answer 4

1. Male
2. Tall with long arms and legs
3. Gynaecomastia
4. Small testes
5. Mental retardation

Question 5

Turner syndrome - phenotype (3)

Answer 5

1. Female
2. Short stature
3. Congenital abnormalities (5 - short stature, web neck, lymphoedema,
   coarctation of aorta, and scoliosis)

Question 6

46XX/46XY - phenotype

Answer 6

Rarest DSD condition, with a higher prevalence in some geographical areas (e.g. Africa)

1. Most cases present with ambiguous genitalia, although clinical presentation may be very variable
2. Degree of genital masculinisation is thought to be a reflection of the amount of functional testicular tissue
3. The gonads can be any mix of ovary, testes and ovotestes, and the etiology is unknown

Question 7

46XX DSD - background

Answer 7

Includes:

1. 46XX with abnormal Mullerian tract development
2. Disorder of gonadal development leading to virilisation
3. Androgen excess

Question 8

Mullerian anomalies - types

Answer 8

1. Prevalence = 1 in 200 women
2. Mullerian anomalies are characterised by abnormal embryological development of the Mullerian ducts and/or persistence of Wolffian structures

Congenital Mullerian abnormalities generally fall into one of three groups:

3. Normally fused single Mullerian system (?) with agenesis of one or more parts
4. Unicornuate systems due to unilateral hypoplasia or agenesis of one Mullerian duct
5. Lateral fusion failures including didelphic (double uterus) and bicornuate (fused lower uterus with two horns) anomalies

Septate and bicornuate anomalies are the commonest of these anomalies

Question 9

Mullerian anomalies - etiology

Answer 9

1. Causes are largely unknown
2. Genetic errors, teratogenic events or combinations of these may contribute
3. Rarely - fhx of similar anomalies
4. Assumed that there has been failure of the two Mullerian ducts, failure of one or both ducts to develop, or failure of resorption of the adjoining areas of Mullerian duct fusion
5. The causes of transverse vaginal septa are unknown

Question 10

Mullerian anomalies - presentation (3)

Answer 10

1. Wide spectrum of anomalous presentations, with 75% of women asymptomatic
2. Secondary sexual development is normal for all women with a Mullerian anomaly, as ovarian development and function are independent of Mullerian duct and urogenital sinus growth
3. Remainder of women have the following presentations (5):
   - Primary amenorrhoea
   - Cyclical abdominal pain, severe dysmenorrhoea (due to obstruction to menstrual drainage from one Mullerian duct)
   - Pelvic mass due to haematocolpos (vagina distended with menstrual blood) or haematometra (uterus distended with menstrual blood), menorrhagia
   - Malodorous vaginal discharge; dyspareunia (with transverse or longitudinal vaginal septa)
   - Infertility or recurrent miscarriage, ectopic pregnancy, obstetric complications (e.g. preterm birth, abnormal lie and uterine rupture)

Question 11

Mullerian anomalies - clinical features in more detail

Answer 11

1. Mayer–Rokitansky–Küster–Hauser (MRKH): painless 1° amenorrhoea,
   normal 2 ° sexual characteristics, blind ending or absent vagina (dimple only).
2. Imperforate hymen: cyclical pain, 1° amenorrhoea, bluish bulging membrane visible at introitus
3. Transverse vaginal septum: cyclical pain, 1° amenorrhoea, possible
   abdominal mass +/– urinary retention due to haematocolpos,
   endometriosis due to retrograde menstruation, not all obstructed, may present with dyspareunia.
4. Longitudinal vaginal septae and rudimentary uterine horns: dyspareunia
   alone if no obstruction, but if one hemi-uterus or hemi-vagina is
   obstructed then increasing cyclical pain in the presence of normal menses +/– abdominal mass from haematocolpos, and endometriosis.
5. Uterine anomalies (bicornuate uterus, arcuate uterus, uterine septae): often asymptomatic, incidental finding at CS, may present with 1 ° infertility, recurrent miscarriage, preterm labour, or abnormal lie in pregnancy (a causal relationship with these conditions is controversial)

Question 12

Embryology of female genital tract - summary

Answer 12

1. Genetic sex determined at fertilisation; sex becomes apparent in normal fetus by 12th week of development
2. By the 6th week of life, the following structures start to develop either side of the midline (3):
   i. Genital ridges (induced by primordial germcells from the yolk sac)
   ii. Mesonephric (Wolffian) ducts (lateral to the genital ridge)
   iii. Paramesonephric (mullerian) ducts (lateral to mesonephric ducts
   In the female fetus, the mesonephric ducts regress.
3. The paramesonephric ducts go on to develop into (2):
   i. Fallopian tubes (upper and middle parts)
   ii. The uterus, cervix and upper 4/5 of the vagina (results from lower part of the ducts fusing together in the midline)
4. The lower 1/5 of the vagina develops from the sinovaginal bulbs of the urogenital sinus (?), which fuses with the paramesonephric ducts
5. The muscles of the vagina and uterus develop from the surrounding mesoderm

What do the genital ridges develop into?

Question 13

Mullerian anomalies - ix

Answer 13

1. Abdominal and TVS are invaluable, but TVS not appropriate if not sexually active
2. MRI is gold standard, especially if complex surgery is planned
3. Examination under anaesthesia +/- vaginoscopy, cystoscopy and hysteroscopy may be required
4. Karyotyping to exclude 46 XY female (androgen insensitivity syndrome) if uterus and upper vagina are absent
5. Renal tract ultrasound should always be undertaken bc high incidence of related renal tract abnormalities (30%)

Question 14

Mullerian anomalies - mx

Answer 14

1. Patients should be given information regarding their condition; support
   groups are often very helpful. Management should be a multidisciplinary approach including
   psychological help for the patient and her parents, as well as arranging correction of anomaly. Asymptomatic anomalies require no treatment
2. Imperforate hymen: easily corrected by a cruciate incision in the
   obstructive membrane
3. Vaginal septae: should be removed surgically. Resection of longitudinal septae usually straightforward; transverse septae can be more complex, especially if high and thick, requiring surgical vaginoplasty
4. Obstructive uterine anomalies should also be surgically corrected or removed. This is usually performed laparoscopically. These procedures can be technically difficult and should only be performed in centres
   with expertise in this area
5. Rokitansky: vaginal dilation is first-line treatment for creating a functional vagina. If this fails, surgical vaginoplasty can be performed by several techniques. Timing should be related to when sexual activity is
   anticipated

Question 15

DSD - presentation

Answer 15

1. Ambiguous genitalia at birth. Genitalia are said to be ambiguous when their appearance is neither that expected for a girl nor for a boy. Incidence approximately 1:4000 births. The extent ranges from mild clitoral enlargement to micropenis with
   hypospadias
2. DSD is not synonymous with ambiguous genitalia. Many conditions will
   present much later.
3. Androgen insensitivity, Swyer syndrome, and Turner syndrome often
   present with 1 ° amenorrhoea.
4. Although often associated with a degree of genital ambiguity,
   5 α -reductase defi ciency and 17 β -hydroxysteroid dehydrogenase
   deficiency may present with virilization at puberty
   ___
5. Never guess the sex of a baby. A full family history, drug hx and whether the mother has experienced any virilization during pregnancy should be ascertained

Question 16

DSD - ix

Answer 16

1. Full assessment of the infant should occur looking for (3):
   i. Evidence of life-threatening salt-losing crisis (adrenal insuffiency), including hypovolaemia, hypoglycaemia, and hyperpigmentation (U&E are essential and must be sent urgently)
   ii. Features of Turner syndrome or other congenital anomalies
   iii. Full inspection of genitalia carefully recording the position of
   orifices
2. Urgent serum 17-hydroxyprogesterone (raised in CAH)
3. 24h urine collection for steroid analysis
4. Karyotyping with urgent FISH for fragments of the Y chromosome
5. Ultrasound to locate gonads and presence of a uterus

Question 17

DSD - corrective surgery

Answer 17

Full disclosure is advocated and parents should be fully informed of the risks of surgery and anaesthesia. These include:
1. Surgery as an infant may not be definitive
2. Each episode of surgery increases the risk of damage to sensitivity of the genitalia and dissatisfaction with sexual function in adult life
3. Such children may one day want to be the opposite sex to that assigned, because of hormonal influences on the fetal brain
4. The need for gonadectomy should be discussed openly with regards to the risk of malignancy, especially for patients with gonadal dysgenesis (30% lifetime risk) or the presence of a Y fragment. In other conditions it may be advocated to prevent further virilization. In AIS, it is advised to delay gonadectomy until after puberty as the malignancy risk is much lower. (?) In all cases parents should be given time to think.
5. Such children should be given age and developmentally appropriate information regarding their condition at an early stage, with psychological
support as required leading up to full disclosure so they can be involved in decisions regarding their care.
____
Other considerations:
1. Timing of surgery is a difficult decision. Traditionally, surgery as an infant was advocated; however, emerging evidence from research and adult patients has led to surgery being deferred until adolescence
2. Aim of surgery is to improve cosmetic appearance of genital area and to provide potentially normal sexual function during adulthood
3. Feminizing genitoplasty is a very complex procedure that requires highly experienced surgeons in a specialized unit
4. As there is a risk of damaging clitoral sensation with surgery consideration must be given to deferring clitoral surgery, especially in mild or moderate clitoromegaly
5. Vaginoplasty can be achieved by a variety of techniques, including a ‘pull-through’ technique, skin flaps, skin grafts, or the use of bowel substitution. To avoid post-operative stenosis regular dilator use
may be required. This is not recommended in children, so delaying surgery may be more appropriate

Question 18

Congenital adrenal hyperplasia - background

Answer 18

1. 46XX. An autosomal recessive condition of enzyme defects in the adrenal steroidogenesis pathways leading to:
   - Cortisol deficiency
   - Increased ACTH secretion with build-up of cortisol precursors
   - Increased androgen production
2. 90% is due to defi ciency of 21- hydroxylase
3. If severe, aldosterone production is also affected leading to salt
   wasting
4. Incidence 1:14 000 births (carrier rate of 1:80)
5. The gene responsible is Cyp21, located on chromosome 6 (but up to 20% cases have no mutation detectable)

Question 19

CAH - clinical features

Answer 19

1. Commonest cause of ambiguous genitalia at birth (responsible for up to 50% of cases)
2. Ambiguous genitalia range from mild clitoral enlargement to a near normal male appearance

Wide spectrum of appearance including:

3. Neonatal salt wasting crisis and hypoglycaemia
4. Childhood virilisation and accelerated growth with early epiphyseal closure -> restricted final height
5. Late-onset with hirsutism and oligomenorrhoea

Note - CAH is the only DSD condition that can be life-threatening, as unrecognised cortisol deficiency can lead to a salt-wasting crisis in the neonate

Question 20

CAH - ix

Answer 20

1. Dx = detection of elevated plasma 17-hydroxyprogesterone
   levels and 24h urinary steroid analysis
2. Conduct other ix for DSD

Question 21

CAH - mx

Answer 21

1. A multidisciplinary approach by paediatric urologists,
   endocrinologists, psychologists, and gynaecologists is required
2. Treatment requires replacement glucocorticoid to suppress ACTH and decrease excess androgen production (whether dexamethasone, hydrocortisone, or prednisolone is used is a balance between risk
   of iatrogenic Cushing’s syndrome and compliance, especially with teenagers). Antiandrogens may be used to combat the effects of raised androgens with lower doses of glucocorticoids.
3. Salt-losing CAH requires fludrocortisone to replace aldosterone.
4. In pregnancy, requirement is increased for both mineralocorticoid and glucocorticoid (placental aromatase converts testosterone to oestradiol protecting the fetus from virilization and destroys exces
   therapeutic hydrocortisone).
5. Prenatal diagnosis is available if a previous child has CAH:
   - Dexamethasone is started with a positive pregnancy test (it crosses the placenta and suppresses the fetal adrenal decreases the severity of ambiguous genitalia)
   - If CVS then shows the fetus is male or negative for the gene mutation, it can be stopped

Question 22

CAH - fertility

Answer 22

1. Menstrual irregularity occurs in:
   - 30% of non-salt-losers
   - 50% of salt-losers
2. Natural fertility:
   - 60% women with non-salt-losing CAH
   - 10% women with salt-losing CAH.
3. Almost all have polycystic ovaries on ultrasound.
4. Fertility treatment should be the same as for women without CAH
5. High levels of progesterone in poorly controlled CAH may be contraceptive by blocking implantation

Question 23

DSD - coping with a child with ambiguous genitalia

Answer 23

1. Keeping parents informed and psychologically supported at a very difficult time is of prime importance.
2. Referral to a dedicated multidisciplinary team is essential
3. Pressure to decide on sex of rearing should not be allowed to interfere with giving time to allow parents to come to terms with their child’s condition or reach the correct diagnosis
4. Parents must be full partners in allocation of sex of rearing
5. Access to relevant support groups is invaluable

Question 24

Androgen insensitivity syndrome (AIS) - background

Answer 24

1. Caused by a mutation in the androgen receptor gene causing resistance to androgens in the target tissues:
   - In the embryo the testis develops normally, but the
   testosterone-dependent Wolffian structures do not
   - AMH is still secreted by the fetal testis, so regression of the Müllerian structures also occurs
2. It has an X-linked recessive pattern in 2/3 of cases (up to 30% de novo mutations). If the mutation can be identified in a family then prenatal diagnosis can
   be offered with CVS.
3. It can be complete (complete androgen insensitivity syndrome, CAIS) or partial (partial androgen nsensitivity syndrome, PAIS)
4. It is the commonest form of under-masculinization in an XY individual
5. Incidence of CAIS is thought to be about 1:20 000, that of PAIS is unclear

Question 25

AIS - clinical features

Answer 25

1. 46 XY but appear female
2. CAIS individuals have (5):
   - Female external genitalia (why - bc failure of virilisation?)
   - A short blind-ending vagina (why - bc regression of Mullerian structures?)
   - Absent uterus and fallopian tubes
   - Normal breast development (why?)
   - Sparse pubic and axillary hair
   Note - in CAIS, physical appearance and core gender identity are both female
3. Presentation can be:
   - Prenatally —fetal karyotype (XY) does not match ultrasound
   findings
   - After birth —inguinal hernias or labial swellings, found to contain testes
   - At puberty: primary amenorrhoea
4. PAIS includes a broad spectrum of under-masculinization ranging from ambiguous genitalia to simple hypospadias
5. The mildest form (mild androgen insensitivity syndrome (MAIS)) will not present until puberty with a high-pitched voice and
   gynaecomastia

Question 26

AIS - dx

Answer 26

1. Karyotype
2. Pelvic U/S (to exclude mullerian structures and locate testes)

Perform other tests for DSD (see DSD ix flashcard)

Question 27

AIS - mx

Answer 27

1. The lifetime risk for malignancy within the testes is thought to be
   about 2% and therefore there is no need for immediate gonadectomy
2. If CAIS is diagnosed before puberty the testes may be left in to allow natural puberty without the need for hormone replacement therapy (HRT) in a child (which assigned gender - male for PAIS?)
3. After puberty:
   - Gonadectomy should be offered because of the difficulty in
   monitoring intra-abdominal testes
   - HRT with oestrogens should be started following gonadectomy
   - Some may require testosterone replacement to feel their best (which assigned gender - male for PAIS?)
4. Bone mineral density should be checked as, even with good
   compliance to HRT, a degree of osteopaenia is noted
5. Once sexual activity is anticipated then vaginal lengthening with the
   use of dilators should be offered. If dilators fail then consider surgical vaginoplasty

___
Coping with the dx of AIS (4):
1. The patient should be referred to a multidisciplinary team
experienced in the management of DSD
2. Input from a psychologist should be offered with an open door policy (disclosure may need to be repeated on subsequent visits)
3. The clinician should offer to explain the condition to the patient’s
relatives or boyfriend
4. Information should be given regarding her diagnosis and referral to
patient support groups offered

Question 28

Gonadal dysgenesis (Swyer syndrome) - overview

Answer 28

1. Results from disruption at very start of male sex determination pathway that causes an XY fetus to divert to the female development pathway (cause?)
2. Result = dysgenetic (abnormally formed) streak gonads
3. As these gonads produce neither AMH nor testosterone, the external genital development is female and the Mullerian ducts develop into the vagina, uterus and cervix
4. Other forms of XY gonadal dysgenesis that can lead to DSD include partial gonadal dysgenesis with some testicular function, and mixed gonadal dysgenesis (a unilateral testis and contralateral streak gonad)
5. These conditions usually present with variable degrees of genital masculinisation or ambiguity

Question 29

Androgen biosynthetic defects - overview

Answer 29

1. May also present with genital ambuiguity at birth
2. Most common = 5 alpha reductase type 2 deficiency and 17 beta hydroxysteroid dehydrogenase type 3 deficiency
3. Both are autosomal recessive conditions in which an XY fetus initially starts down the male development pathway with normal testicular develop
4. However, there is a deficiency of enzymes involved in androgen synthesis, leading to a variant of female external genital development (failure of virilisation)
5. If left untreated in childhood, both conditions will result in increasing masculinisation at puberty, and possibly a change in gender identity from female to male for some individuals