3 Beta-hydroxysteroid dehydrogenase type 2 Deficiency

The adrenal glands, together with the testicles and ovaries, are organs responsible for the production of hormones. In some conditions, it may happen that the enzymes –i.e. the proteins necessary for the production of some hormones– fail to work properly, in which  case the adrenal glands may increase in volume (adrenal hyperplasia) to compensate for it. This compensatory mechanism will increase the production of some hormones and bring them to an adequate level, but it can also lead to an excess in the production of others. In the adrenal glands, 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) enzyme is essential for the production of cortisol, aldosterone, and androgens (dehydroepiandrosterone and delta4-androstenedione). This enzyme enables an essential step of the synthesis of testosterone in the testicle. If due to a genetic mutation this enzyme is deficient, a very rare form of congenital adrenal hyperplasia occurs, of which less than 200 cases are known worldwide. The estimated incidence is less than 1:1,000,000 people born alive.

The clinical presentation of this Variation of Sex Characteristic (VSC)/Difference of Sex Development (DSD) varies according to the severity of the mutation. If the genetic mutation completely inactivates the 3βHSD2 enzyme, the deficiency of the hormones cortisol and aldosterone can cause a syndrome characterized by low blood pressure, weakness, and abundant loss of salt (sodium) with urine. So much so that the clinical picture is commonly referred to as “salt loss” or “classical form”.  If unrecognized, this syndrome can lead to the death of the newborn. When the activity of the enzyme is only reduced, there is no “salt loss”; however the altered synthesis of sex steroids still remains. In individuals with chromosomal sex 46,XY, the prevalent manifestation is testosterone deficiency and the ensuing reduced virilization, which can manifest at birth with atypical external genitalia, i.e. different from those typically considered male or female. 

During childhood, the premature appearance of axillary and pubic hair, and the appearance of glandular breast tissue (gynaecomastia) are common. Both early and delayed pubertal development vs. what is generally expected (within 14 years for individuals assigned male at birth, and 13 years for individuals assigned female) have also been found. Individuals with chromosomal sex 46,XX exhibit excessive virilization due to an overproduction of testosterone precursors. At birth, genital ambiguity is mild (mostly an increase in the size of the clitoris or clitoromegaly); during the pubertal and post-pubertal stage premature pubarche (early appearance of pubic hair), hirsutism (abnormal presence of hair), menstrual disorders such as the absence of menstruation (amenorrhea) may occur.

Genetic traits
This condition is due to the genetic mutation of the 3β-HSD2 gene, coding for the homonymous enzyme. To date, approximately  40 variants of the gene have been found.

Identification
In most of the cases described in the scientific literature, the variant is identified perinatally (often in the first weeks of life, when “salt loss” occurs) or before puberty. In 46,XX individuals, the nuanced picture of genital atypia at birth can delay or prevent recognition; in children with 46,XY chromosomes, where genital atypia is more marked, the condition can be recognised  earlier and more  easily. Some hormonal assays can highlight, especially in the child with 46,XY karyotype, a testosterone deficiency or an insufficient production of cortisol and aldosterone, as well as a compensatory increase in their hormonal precursors. In adults, testosterone levels can be normalized thanks to the mechanisms of compensation for enzymatic deficiencies. In any case, the search for the specific genetic mutation is almost always necessary, even to distinguish 3βHSD2 deficiency (3β-HSD2D) from other intersex conditions.

Medical options
Some infants with 3β-HSD2D and “salt loss” need hormone replacement therapy for cortisol and aldosterone deficiency to avert serious short- and long-term consequences on their general health. This may be a life-long treatment.
Even without severe clinical problems in the perinatal period (in forms without “salt loss”), the problem of assigning a gender at birth may arise, especially in newborns with 46,XY karyotype with genital atypia. In most cases reported in the scientific literature, the infants were assigned to the male gender. Obviously, only the individual will be able to express their gender identity, which may or may not be congruent with the gender assigned at birth. Therefore, the most recent recommendations lean towards postponing partially reversible or irreversible interventions (including any surgery aimed at the feminization or masculinization of the genitals) to a moment in which the person can express their informed consent. Some individuals with 3β-HSD2D may require hormonal therapy to delay puberty if it begins too early, to reach an adequate final height; in rare occasions, others may instead benefit from hormonal therapy to induce puberty. The need for hormone replacement therapy in adults is also rare. In people with 3β-HSD2D, adrenal rests (benign masses of adrenal glandular tissue) can grow in the gonads (mostly in the testicles, very rarely in the ovaries). As they can damage the testicle, after puberty they must be monitored by ultrasound. In 46,XY individuals, seminal fluid production can be severely impaired;  fertility may be reduced also in 46,XX individuals, especially if there is menstrual irregularity. However, there is not enough data available to draw definitive conclusions regarding the fertility potential of individuals with 3β-HSD2D.

Bibliography 
Al Alawi AM, Nordenström A, Falhammar H. Clinical perspectives in congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase type 2 deficiency. Endocrine. 2019 Mar;63(3):407-421
Domenice S, et al. 46, XY Differences of Sexual Development. Last Update: 2022 Aug 21. In: Endotext [Internet]
Guran T et al. Revisiting Classical 3β-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases. The Journal of clinical endocrinology and metabolism. 2020 Mar 1;105(3):dgaa022

Further Links
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