17 Beta-hydroxysteroid dehydrogenase type 3 Deficiency

During the development of a fetus with chromosomes 46,XY, the testes produce androgens (i.e., male hormones) that give genitals typically male characteristics. Owing to a genetic mutation, the enzyme that produces testosterone –17 beta-hydroxysteroid dehydrogenase type 3 (HSD17B3)-- may be less functional, and reduce the production of testosterone at various stages of life. In particular, female or atypical genitalia (i.e., those not typically considered either male or female) are generally present at birth. The testicles are located in the inguinal canal or the abdomen rather than in the scrotum. At puberty, virilisation occurs, i.e., there appear some typically male sexual characteristics, for example the lowering of the vocal timbre or the development of muscle mass. This happens because at this stage the stimulus for hormone production in the testicle is so strong that testosterone levels increase despite the defect in its production chain. This is the most common mutation underlying altered androgen synthesis, and accounts for about 4% of all forms of Variations of Sex Characteristic (VSCs)/Differences of Sex Development (DSDs). Parental consanguinity is a risk factor.

Genetic traits
The variation is due to a mutation in the HSD17B3 gene, coding for the HSD17B3 isoenzyme. To date, about 40 variants of the gene have been reported.

Identification
The variation is largely recognised clinically at birth or at puberty. At birth, most infants are assigned to the female sex (AFAB); sometimes, the only features that bring the subject to the physician's attention are the increased size of the clitoris or the presence of an inguinal hernia.
At puberty, the AFAB person with HSD17B3D comes to the physician’s attention because development does not proceed along female lines (e.g., the first menstrual cycle does not appear), and male characteristics are manifested (lowered vocal timbre, increased body hair, development of muscle mass and increased clitoral volume). An increase in mammary gland volume is frequent, though. Hormonal assays can assist in variant identification, although they are often unreliable in this case. A genetic study is therefore indispensable.

Medical options
Newborns with HSD17B3 do not have health threatening hormonal deficits. On the other hand, the question of gender assignment may arise. Most people with this type of VSCs/DSDs are assigned to the female gender at birth, but it is very common for changes in gender identity and/or gender expression to occur at puberty. In general, international recommendations favour male gender assignment at birth, especially if VSCs/DSDs is diagnosed early. Obviously, only the person will later be able to express their gender identity, which may or may not be congruent with the gender assigned at birth. Accordingly, more recent recommendations advocate postponing partially reversible or irreversible medical-surgical interventions that are not medically necessary to a time when the person will be able to express their informed consent to any action involving their body. That being said, according to the general recommendations for the care of persons with VSCs/DSDs, if during puberty the person reports a female gender identity and desire for affirmation treatment, the ideal would be to undertake hormone therapy to simulate female pubertal development, and then continue with replacement therapy in adulthood. Some people may wish to have surgery to feminise their genitals, also to ensure an adequate sexual and urinary function. Others with HSD17B3D and male gender identity may desire gender affirmation congruent with their gender identity. Testosterone therapy may be necessary to achieve complete virilisation. Gender affirmation surgery may also be required to optimise the appearance and/or function of external genitalia or the ability to urinate. A yearly ultrasound examination of the testicles will be necessary, as the risk of testicular cancer has been found to be higher than in the general population. In any case, based on the scientific data currently available, removal of the testicles is not recommended just to avoid tumour risks. In people with HSD17B3D, the testicles are seldom located in the scrotum at birth, but rather on the groin, which often results in an impairment of their ability to produce sperm (as well as contributing to the increased risk of cancer). Therefore, these people are usually unable to conceive spontaneously, but can do so through medically assisted procreation (MAP) techniques.

Bibliography
Cools M et al. Caring for individuals with a difference of sex development (DSD): a Consensus Statement. Nature Reviews. Endocrinology. 2018 Jul;14(7):415-429
Domenice S et al. 46,XY Differences of Sexual Development. Last Update: August 21, 2022. In: Endotext [Internet]
Mendonca BB et al. 46,XY disorder of sex development (DSD) due to 17β-hydroxysteroid dehydrogenase type 3 deficiency [Abstract]. The Journal of Steroid Biochemistry and Molecular Biology. 2017;Jan;165(Pt A):79-85

Further information
Orphanet. 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency