Disorders of Sex Development

Overview

Ambiguous genitalia describes congenital birth defects in which the outer genitals do not have the typical appearance of a boy or girl. They are caused by abnormalities in chromosomal, gonadal, or anatomical sex. The conditions causing these are known as disorders of sex development (DSDs), formerly known as intersex conditions.

Embryology

Initially, gonads in the foetus are undifferentiated. On the Y chromosome, the sex-determining region Y protein (SRY) gene causes the differentiation of the gonad into a testis. If the SRY gene is absent, then the gonad differentiates to become an ovary.

In the testis:

• Sertoli cells secrete anti-Müllerian hormone (AMH):
  • This leads to regression of the Müllerian ducts, which develop into female reproductive organs
• Leydig cells secrete testosterone which:
  • Leads to the development of the mesonephric duct (Wolffian duct) into male reproductive organs (vas deferens, epididymis, and seminal vesicles)
  • Is converted by 5-alpha reductase into dihydrotestosterone (DHT) which leads to the development of the penis and scrotum

In the ovary:

• There is no AMH, so the Müllerian ducts persist and develop into the uterus, fallopian tubes, and upper 1/3 of the vagina
• The vaginal plate forms from the ends of the Müllerian ducts which contributes to the development of the lower 2/3 of the vagina, clitoris, labia minora, and labia majora. 

Categories

Overview

Terms previously used such as ‘intersex’, ‘hermaphrodite’, and ‘pseudohermaphrodite’ have been abandoned due to confusion and stigma. DSDs are categorised into:

• 46,XX DSD:
  • Genetic female sex chromosomes but virilisation is present
  • The most common cause is congenital adrenal hyperplasia (CAH)
• 46,XY DSD:
  • Genetic male sex chromosomes but impaired virilisation is present (e.g. micropenis, atypical or female genitalia)
  • Causes include hypospadias and androgen insensitivity syndrome (AIS)
• Ovotesticular DSD:
  • This describes the presence of both ovarian and testicular tissue
• 46,XX testicular DSD:
  • Genetic female chromosomes but male in appearance
  • Causes include translocation of the SRY gene to the X chromosome or copies or rearrangements of the SOX9 or SOX3 gene
• 46,XY complete gonadal dysgenesis:
  • Genetic male sex chromosomes but the person is externally female with small and underdeveloped gonads with little gonadal tissue (streak gonads). These streak gonads are surgically removed due to an increased risk of cancer.

Epidemiology

• Genital anomalies are estimated to occur in up to 1 in 4500 births
• The most common cause of ambiguous genitalia is congenital adrenal hyperplasia (CAH)
• Mixed gonadal dysgenesis is the next most common cause

General Features

Overview

Most disorders of sex development are identified at birth due to ambiguous genitalia, however, some people may be diagnosed later on in life, such as during puberty if phenotypic females with underlying 46,XY chromosomes have primary amenorrhoea.

Infants with ambiguous genitalia should be treated urgently as an emergency with immediate assessment as congenital adrenal hyperplasia (CAH) can have salt-wasting crises which can cause hypotension, shock, and death.

Features

General features suggesting DSDs include:

• Male appearance but abnormal genitalia such as:
  • Undescended testes – especially if bilateral or with hypospadias
  • Hypospadias with a bifid scrotum
  • Bilateral non-palpable testis and full-term
• Female appearance but abnormal genitalia such as:
  • Clitoral hypertrophy
  • Non-palpable gonads
  • Vulva with a single opening
• A baby with ambiguous genitalia where it is impossible to identify if they are male or female

Diagnosis

Diagnosis is made with care by a multidisciplinary team including geneticists, paediatric endocrinologists, gynaecologists, psychologists, neonatologists etc.

General investigations may include:

• Pelvic ultrasound:
  • Identifies the presence or absence of undescended testes, uterus, or the ovaries
• Urea and electrolytes:
  • To identify congenital adrenal hyperplasia and potential salt-wasting
  • May show low sodium and/or high potassium
• Karyotyping:
  • Identifies genotype