Embryological background
Primitive sex cords form during the 6th week.
The default is to develop as a female. The development of male genitals is due to the influence of SRY (sex determining region of the Y chromosome).
SRY induces cells in the primitive sex cords to differentiate to Sertoli cells.
Without SRY, the primitive sex cords differentiate to ovarian follicles.
During week 7, the Sertoli cells organise to form testis cords which progress to form seminiferous tubules and rete testis.
Developing Sertoli cells then produce Mullerian inhibiting substance (MIS or anti-Mullerian hormone AMH) causing regression of the Mullerian (paramesonephric) ducts.
SRY also causes genital ridge differentiation into Leydig cells which secrete testosterone between 8th and 12th weeks.
The genitals form from the urogenital folds and labioscrotal folds with development based on the presence or absence of the signalling via the androgen receptor.
In the presence of fetal androgens/testosterone (from Leydig cells) – the mesonephric (Wolffian) ducts persist as epididymis, vas and SVs, with both testosterone and DHT interacting with androgen receptors to drive growth of external genitalia and prostate.
Absence of androgen receptor stimulation leads to failure of the perineum to length and no fusion of the labioscrotal folds and urethral folds -> labia.
Presentations
Neonates with ambiguous genitalia:
- Atypical genitalia
- Bilateral non palpable gonads (uterus may be found at laparoscopy)
- Palpable gonads in labioscrotal folds
- Perineal hypospadias with undescended testis
- Undervirilised phallus
- Clitoromegaly
- Discordance with antenatal NIPT
In childhood or adolescence:
- Rapid growth spurt / exaggerated adrenarche
- Virilisation of female genitalia / clitoromegaly
- Primary amenorrhoea
- Abnormal gonads at laparoscopy
Classification
- 46 XX DSD (genetically female, overvirilised phenotype)
CAH most common cause.
Disorders of ovarian development or androgen excess.
- 46 XY DSD (genetically male, undervirilised phenotype)
Complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS)
5 alpha reductase deficiency
Disorders of testicular development
AMH disorders (persistent Mullerian duct syndrome)
Severe hypospadias, cloacal exstrophy
- Sex chromosome DSD (atypical arrangement of sex chromosomes)
Klinefelter syndrome 47 XXY
Turner syndrome 45 XO
Other mosaics, mixed gonadal dysgenesis
Ovotesticular DSD – discrete both female and male anatomic elements – may be XY or XX, may be one of each on each side etc.
Work-up of the newborn with ambiguous genitalia
History:
- Antenatal issues – scan results, NIPT results if available, other identified issues
- Family history of any relevant conditions
- Child’s progress from birth to now – other medical concerns or issues identified
Examination:
- General state and condition
- Hydration state
- Blood pressure
- Appearance of genitalia
- Labioscrotal folds / fusion or bifid scrotum
- Palpable gonads and where are they located
- Urethral meatus
- Size of penis or clitoris
Investigations / work-up (usually led by paediatric endocrinologist)
- Electrolytes
- Karyotype – FISH or rapid PCR looking for Y
- 17-OHP (17-hydroxyprogesterone)
- Testosterone, oestradiol, gonadotropins, DHT
- Serum AMH
- Imaging controversial and bespoke
- Pelvic USS – ?is there a uterus – not specific or sensitive for gonads
- MRI – similar issues with sensitivity
- Laparoscopy occasionally needed
Issues and management principles
Goals of early management:
- Identify and treat emergent medical issues i.e. salt-losing CAH
- Establish a diagnosis
- Determine sex of rearing (in conjunction with MDT)
DSD should be managed in a multidisciplinary team – endocrine, urology, gynaecology, ethicist, genetics, specialist nursing, psychology, GP.
Principles of management:
- Multi-disciplinary
- Patient-focussed
- Acknowledge and accept uncertainty
- Agree on a gender – allowing for potential later change
- Minimise irreversible interventions
- Psychological support for young person and family
Issues with DSD management:
- Timing of any surgery
- Weighing up functionality, prevention of malignancy and cosmesis
- Removal of gonads solely to align with sex of rearing no longer standard practice. Advocacy groups preference to defer any ‘non-therapeutic’ surgery.
- Early surgery – little memory for patient, parents may be reassured – but consent issues, risk of dysphoria and regret
- Later – may allow more input from patient, but may have issues in childhood, easier to use vaginal dilators etc, psychological effect
- Controversial and best discussed in MDTs with ethicists etc – defer if safe
- Malignancy risk
- Highest risk is gonadal dysgenesis (intra-abdominal testis), partial androgen insensitivity syndrome with non-scrotal testis (50 %), Frasier syndrome and Denys-Drash
- Fertility implications
- Psychosocial follow up and risk of gender dysphoria
- Transitional care as adolescent
A child is unable to consent to a surgical procedure until they are Gillick competent and can understand the consequences. Until then, parents or legal guardians give consent (provided they are fully informed and make the decision in the childs best interest).
MDTs may allow deferral of surgical procedures not deemed medically necessary until the child may be able to provide input.
Congenital adrenal hyperplasia
Arises from one of three enzymatic defects affecting the biosynthetic pathways for production of cortisol and aldosterone in the adrenal gland.
End result is overproduction of ACTH which stimulates overproduction of androgen pre-cursors by adrenals
Hence overvirilised female genitalia / ambiguous genitalia
Most common is 21-hydroxylase deficiency which is autosomal recessive.
- Diagnosed by elevated serum 17-hydroxyprogesterone (17-OHP)
Half of cases are salt losing (hyperkalaemia, hyponatraemia, hypotension) – potentially life threatening
- Managed with glucocorticoid and mineralocorticoid replacement, IV hydration, endocrine led
- Usually female sex of rearing with feminising genital surgery (?best delayed)
The other two types are 11-b hydroxylase deficiency or 3b hydroxysteroid dehydrogenase deficiency.