Differences in sex differentiation

Key points

Incidence/Prevalence

1 in 5000

125-150/y in UK

Commonest cause of ambiguous genitalia in newborn is Congenital adrenal hyperplasia (CAH)

Categorisation (Chicogo 2006)

46 XY undervirilised male

• Complete androgen insensitivity syndrome (CAIS)

• Partial androgen insensitivity syndrome (PAIS) - may present with the complete spectrum of normal male to female genitalia

• Complete gonadal dysgenesis (Swyer syndrome) - no testosterone or AMH

• 5a reductase deficiency - raised as girl but virilised in puberty

• Antimullerian hormone (AMH) deficiency or insensitivity AKA persistent mullerian duct syndrome - may present with bilateral undescended testes + uterus + fallopian tubes

46XX overvirilised female

• CAH - 90% are 21 hydroxylase deficiency - Autosomal recessive

• Aromatase deficiency

• Maternal luteoma or exogenous androgens

Sex chromosome

• 45X Turners

• 47 XXY Klinefelters

• 45X/46XY Mixed gonadal dysgenesis - one streak gonad and 1 dysgenetic testis. Often Hypospadias. Internal anatomy variable

• 46XX/XY Chimeric Ovotesticular DSD - can have one of each ovary and testis, or different at poles, or complete mix. Ambiguous genitalia

SRY gene - short arm of Y - testes

Sertoli cells - produce AMH

Leydig cells - produce testosterone

The first sign of male phenotypic differentiation is the degeneration of the müllerian ducts adjacent to the testes weeks 7-8

Scoring systems

External masculinisation score <11 = DSD

Prader stages for girls

External genital score <10.5: DSD - most recent - need to take measurements

Operation

Genitoplasty during childhood is no longer recommended in the UK

Example procedures:

Male genitoplasty - similar to hypospadias repair

Clitoroplasty

Preserve dorsal neurovascular bundle

Corpora then resected or rotated into labia

Glans partially de-epithelialised and buried

Vaginoplasty

U shaped flap advanced in posteriorly

Alternatives:

Partial urogenital mobilisation (patients may have urogenital sinus) Partial - anterior dissection does not go above pubic bone

Anterior sagittal transanorectal approach (ASTRA) - only anterior wall of rectum divided

Buccal mucosal graft

Standard scenario

Concerns in DSD in general:

1. Salt wasting if neonate with CAH

2. Psychological impact

3. Later: Management of gonads and cancer risk

4. If uterine structure - may need channel for products of menstruation to drain

5. Later: Genitoplasty - but not often done unless functional problem or if older child wants it with MDT approval

6. Impact on future pregnancies

History:

General antenatal features

Co morbidities

Examination:

General dysmorphic features

Genitalia- using neutral terminology

Palpate for gonads

Symmetry- suggests biochemical DSD

Asymmetry suggests mosaicism

Differential ? Perineal hypospadias

Explain to parents using neutral terms

Example “I can feel a lump in your baby’s groin, it might be a hernia or a gonad. There are many causes of this, one of which is could be a chromosomal cause, so to start I would like to get a chromosomal test and an USS to look at the anatomy”

Investigations

FISH for Y material + Karyotype

17 OHP

USS for genitourinary tract abnormalities

Serum + urinary sex hormone+ steroid profiles - LH/FSH, testosterone + oestrogen + urinary steroid profile

If neonate with suspected CAH - daily UE + glucose for salt wasting crisis for 3 weeks

Refer to MDT

Medical management of hormones

Do not offer genitoplasty during childhood

All CAH need lifelong hydrocortisone replacement +/- fludrocortisone if salt wasting

Specific management depending on presence of Y material in gonad and chosen gender

46 XY undervirilised OR Sex chromosome

If female:

CAIS - post pubertal gonadectomy

PAIS - peripubertal gonadectomy

Sex chromosome (including 45X+Y) Gonadectomy early if high risk, can wait if low risk

If male:

Orchidopexy + biopsy 1 side pre-pubertal and bilateral post pubertal

If malignancy - gonadectomy or irradiation

In all cases consider cryopreservation

If unclear gender identity or if unsure presence of Y chromosome material - bilateral biopsy + MDT

46XX virilised - No need for gonadectomy - will have mullerian structures

Persistent Mullerian duct syndrome

Take to MDT

Leave mullerian structures alone unless symptomatic/complications - risk of damage to adherent vas

Orchidopexy

No fertility if Y chromosome

If severe hypospadias bilateral palpable gonads - do FISH + Karyotype but likely Hypospadias

If unilateral palpable gonads - treat as DSD

Diagnostic paradigm is whether 46XY DSD is present

Treatment paradigm is if raised as male - how to manage hypospadias + gonads

References

Hughes IA, Houk C, Ahmed SF, Lee PA; LWPES Consensus Group; ESPE Consensus Group. Consensus statement on management of intersex disorders. Arch Dis Child. 2006 Jul;91(7):554-63. doi: 10.1136/adc.2006.098319. Epub 2006 Apr 19. PMID: 16624884; PMCID: PMC2082839.

Essentials of Pediatric Urology, 3rd edition, 2022, Chapter 20 Disorders of Sex Development

van der Zwan YG, Biermann K, Wolffenbuttel KP, Cools M, Looijenga LH. Gonadal maldevelopment as risk factor for germ cell cancer: towards a clinical decision model. Eur Urol. 2015 Apr;67(4):692-701. doi: 10.1016/j.eururo.2014.07.011. Epub 2014 Sep 18. PMID: 25240975.