17 alpha ketosteroid reductase deficiency of testis,[1] 46,XY difference of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency, 17-ketoreductase deficiency, 17-ketosteroidreductase deficiency.
Biochemical effects of 17β-hydroxysteroid deficiency-3 in testosterone biosynthesis. Typically levels of androstenedione are significantly increased, whilst testosterone levels are decreased, leading to male
undervirilization.
The autosomal recessive deficiency arises are a result of homozygous or compound heterozygous mutations in
HSD17B3 gene which encodes the
17β-hydroxysteroid dehydrogenase III enzyme, impairing of the conversion of 17-keto into 17-hydroxysteroids. The enzyme is involved in the last phase of
steroidogenesis and is responsible for the conversion of
androstenedione to
testosterone and
estrone to
estradiol.
Virilization of affected males still occurs at puberty.[8]
Genetics
17β-Hydroxysteroid dehydrogenase III deficiency is caused by
mutations found in the 17β-HSD III (
17BHSD3) gene.17β-HSD III deficiency is an autosomal recessive disorder.[3][9]
A deficiency in the HSD17B3 gene is characterized biochemically by decreased levels of
testosterone which results in the insufficient formation of dihydrotestosterone during fetal development. During the expected time of puberty, there is an increase in plasma luteinizing hormone and, consequently, in the testicular secretion of androstenedione. This leads to a clinically important higher ratio of
androstenedione to testosterone.[11][3][12]
However, significant amounts of the circulating androstenedione are converted to testosterone causing virilization.[citation needed]
Diagnosis
In terms of the diagnosis of 17β-hydroxysteroid dehydrogenase III deficiency the following should be taken into account:[4][7]
The 2006 Consensus statement on the management of intersex disorders states that individuals with 17β-hydroxysteroid dehydrogenase III deficiency have an intermediate risk of germ cell malignancy, at 28%, recommending that gonads be monitored.[5] A 2010 review put the risk of germ cell tumors at 17%.[13]
The management of 17β-hydroxysteroid dehydrogenase III deficiency can consist, according to one source, of the elimination of
gonads prior to
puberty, in turn halting
masculinization.[7]
Hewitt and Warne state that, children with 17β-hydroxysteroid dehydrogenase III deficiency who are raised as girls often later identify as male, describing a "well known, spontaneous change of gender identity from female to male" that "occurs after the onset of puberty."[14] A 2005 systematic review of gender role change identified the rate of gender role change as occurring in 39–64% of individuals with 17β-hydroxysteroid dehydrogenase III deficiency raised as girls.[15]
Society and culture
Modification of children's sex characteristics to meet social and medical norms is strongly contested, with numerous statements by civil society organizations and human rights institutions condemning such interventions, including describing them as harmful practices.[16][17][18]
A 2016 case before the
Family Court of Australia[19] was widely reported in national,[20][21][22] and international media.[23] The judge ruled that parents were able to authorize the sterilization of their 5-year-old child reported only as "Carla". The child had previously been subjected to
intersex medical interventions including a
clitorectomy and
labiaplasty, without requiring Court oversight - these were described by the judge as surgeries that "enhanced the appearance of her female genitalia".[19]Organisation Intersex International Australia found this "disturbing", and stated that the case was reliant on
gender stereotyping and failed to take account of data on cancer risks.[24]
^
abcMendonca, Berenice B.; Gomes, Nathalia Lisboa; Costa, Elaine M.F.; Inacio, Marlene; Martin, Regina M.; Nishi, Mirian Y.; Carvalho, Filomena Marino; Tibor, Francisco Denes; Domenice, Sorahia (January 2017). "46,XY disorder of sex development (DSD) due to 17β-hydroxysteroid dehydrogenase type 3 deficiency". The Journal of Steroid Biochemistry and Molecular Biology. 165 (Pt A): 79–85.
doi:
10.1016/j.jsbmb.2016.05.002.
PMID27163392.
S2CID25083887.
^Pleskacova, J.; Hersmus, R.; Oosterhuis, J.W.; Setyawati, B.A.; Faradz, S.M.; Cools, M.; Wolffenbuttel, K.P.; Lebl, J.; Drop, S.L.; Looijenga, L.H. (2010). "Tumor Risk in Disorders of Sex Development". Sexual Development. 4 (4–5): 259–269.
doi:
10.1159/000314536.
ISSN1661-5433.
PMID20558977.
S2CID1847011.
^Hewitt, Jacqueline K.; Warne, Garry L. (February 2009). "Management of disorders of sex development". Pediatric Health. 3 (1): 51–65.
doi:
10.2217/17455111.3.1.51.
ISSN1745-5111.
^Cohen-Kettenis, Peggy T. (August 2005). "Gender Change in 46,XY Persons with 5α-Reductase-2 Deficiency and 17β-Hydroxysteroid Dehydrogenase-3 Deficiency". Archives of Sexual Behavior. 34 (4): 399–410.
doi:
10.1007/s10508-005-4339-4.
ISSN0004-0002.
PMID16010463.
S2CID146495456.