17 alpha-hydroxylase / 17-20 lyase Deficiency

Adrenal glands, testicles, and ovaries are the organs that produce hormones. However, under certain conditions, the adrenal enzymes –substances involved in hormone production– may not function properly. To compensate for this, adrenal glands may increase in volume (adrenal hyperplasia). This mechanism successfully produces some hormones, but can lead to an excess production of others. In the adrenal glands, the enzyme 17-20 lyase is necessary for cortisol and androgen synthesis, while in the testes and ovaries, it is required for androgen and, indirectly, oestrogen synthesis. Deficiency in this enzyme causes a rare form of Congenital Adrenal Hyperplasia (CAH). Individuals with a typical male karyotype (46, XY) show a deficiency in testosterone, leading to reduced virilisation. At birth, this may be evident with atypical external genitalia (not clearly identifiable as typically male or female) often associated with undescended testicles in the abdomen. Individuals with a typical female karyotype (46, XX) have typically female internal and external genitalia at birth. However, in adolescence, pubertal development usually does not begin, specifically there is no first menstrual cycle. Other typical manifestations of this Variation of Sex Characteristic (VSC)/Difference of Sex Development (DSD) include high blood pressure and low potassium levels (hypokalemia) due to an excessive production of the hormone corticosterone. This generally occurs after the weaning of the child, regardless of karyotype.

Genetic traits
The condition is caused by a mutation in the CYP17A1 gene, located on chromosome 10.

Identification
In some cases, individuals with a 46,XY karyotype are assigned to the female gender at birth based on the appearance of their external genitalia. Later on they seek medical attention due to the absence of menstruation (primary amenorrhoea) and lack of breast development. Similarly, for individuals with a 46,XX karyotype, the first medical consultation is associated with the missing onset of puberty. From a hormonal perspective, the condition is characterized by reduced levels of 17-hydroxyprogesterone, cortisol, androgens, oestrogens, renin, and aldosterone; while there are high levels of progesterone and corticosterone.
The condition is not the same as complete gonadal dysgenesis: a helpful element for differential diagnosis is the presence of high blood pressure and the absence of pubic and axillary hair in 17-20 lyase deficiency.

Medical Options
Regardless of the gender assigned at birth, chronic therapy with corticosteroids is generally required to regulate the excess of the hormone corticosterone, normalizing blood pressure and potassium levels. However, corticosteroid therapy in children can have detrimental effects on height growth and bone health, necessitating careful assessment and follow-up to minimize the side effects of treatment. At birth, the question of gender assignment may arise for neonates with a 46, XX karyotype and genital atypia. In most reported cases, they have been assigned female at birth and have affirmed a female gender identity. Only individuals can express their gender identity, whether it aligns with the gender assigned at birth or not. Consequently, recent recommendations emphasize the need to postpone partially reversible or irreversible interventions (including potential surgical procedures for genital feminization or masculinization) until the person is capable of providing informed consent. Hormone therapy (oestrogens or testosterone) is often required to induce puberty congruent with the individual's gender identity. Hormone replacement therapy must be maintained into adulthood for overall health and bone health. In individuals with a 46,XY karyotype seeking feminising therapy, an oestrogen-based treatment can be prescribed, while those with a 46,XX karyotype (whose gender identity is generally female) require oestrogen and progestin therapy to ensure uterine health. For individuals with a 46,XY karyotype and abdominal testicles, there may be an increased risk of developing testicular tumours after puberty. Therefore, regular testicular ultrasound examinations are prescribed. Based on current scientific data, testicular removal is not recommended just because of the risk of tumour development. The deficiency of the 17-20 lyase enzyme is associated with infertility due to an altered production of oestrogens and testosterone, required for the production and maturation of germ cells in both the ovary and testicle. Despite this, rare cases of individuals with a 46,XX karyotype achieving pregnancies through medically assisted reproduction techniques have been reported. As of now, there are no known successful cases of infertility treatment in individuals with a 46, XY karyotype.

Bibliography
Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. [Abstract] Endocrinology and Metabolism Clinics of North America. 2001 Mar;30(1):101-19, vii 
Domenice S et al. 46,XY Differences of Sexual Development. Last Update: August 21, 2022. In: Endotext [Internet]
Marsh CA, Auchus RJ. Fertility in patients with genetic deficiencies of cytochrome P450c17 (CYP17A1): combined 17-hydroxylase/17,20-lyase deficiency and isolated 17,20-lyase deficiency. Fertility and Sterility. 2014 Feb;101(2):317-22

Further Links
Orphanet. Iperplasia surrenalica congenita da deficit di 17-alfa-idrossilasi
MedLine Plus. 17 alpha-hydroxylase/17,20-lyase deficiency