46,XX-DSD

46,XX-DSD / Congenital adrenal hyperplasia (CAH)

Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders of the adrenal glands that can affect both boys and girls. The adrenal glands are responsible for producing the following hormones:

  • Cortisol, which regulates blood pressure, glucose and the body’s response to illness or stress
  • Mineralocorticoids, such as aldosterone, which regulate sodium and potassium levels
  • Androgens, such as dihyroepiandrostenedione (DHEA), which are weak sex hormones.When significantly elevated these androgens may induce virilisation of the female external genitals.

A defect in one of the enzymes involved in the adrenal steroid synthesis will make the body unable to produce cortisol and often also aldosterone, which in turn will result in the overproduction of androgens and accumulation of other hormone precursors before the enzymatic block.

The most common cause of CAH is a defect of the enzyme 21-hydroxylase (21 hydroxylase deficiency (21OHD), which can present as severe or mild forms depending on the underlying mutation: Classical 21OHD, which can be sub-divided into the salt-losing form or the simple-virilising form, and non-classical CAH.

Classical 21OHD, the severe form, is characterised by cortisol deficiency and detected in the neonatal period. The most severe form of classical 21-OHD, the salt-wasting form, additionally is characterised by aldosterone deficiency and leads to life-threatening salt-wasting crises in the first weeks of life if not detected and adequately treated. Patients with the simple virilising form are also at risk for adrenal crises due to lack of cortisol. Therefore, neonatal screening has been introduced in many countries all over the world.

In addition, in girls with classical 21OHD, the increased secretion of pituitary ACTH due to the lack of the negative feedback of cortisol on the pituitary gland leads to chronic stimulation of the adrenal gland with consequently increased production of the unaffected androgen pathway and thus to a variation of female sex differentiation, which is called 46,XX DSD (Difference of Sex Development). In affected girls, virilisation, the formation of an androgenised external genitalia with clitoral hypertrophy and fusion of vagina and urethra occurs already prenatally. The uterus and ovaries are not affected.The severity of virilisation is often determined according to Prader and divided into 5 stages. The changes can range from a slight enlargement of the clitoris to the formation of a phallus that resembles a penis. Depending on the severity, genital correction may be necessary or desired. Due to the different legal situations in the respective European countries, additional consultations and authorisations are sometimes required for the protection of the children.

Non-classical 21OHD, the milder form and more common, may not become evident until childhood or early adulthood Symptoms are mostly evident in girls who present with acne, hirsutism or irregular menstruation.Although 21OHD is not curable, as long as patients receive adequate care and treatment, they can go on to lead normal lives and good quality of life can be achieved.21OHD is treated by lifelong substitution of glucocorticoids and, if necessary, mineralocorticoids.Below you will find:

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(Source references: Patient organisation website, endocrinology/paediatric societies, endrocrinologists/paediatricians, RC,NORD)

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