17β-Hydroxysteroid dehydrogenase III deficiency is a rare

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

disorder of sexual development condition that is a cause of 46,XY disorder of sex development (46,XY DSD). The impaired

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

biosynthesis by

17β-hydroxysteroid dehydrogenase III 17β-Hydroxysteroid dehydrogenase 3 (17β-HSD3) is an enzyme that in humans is encoded by the ''HSD17B3'' gene and is involved in androgen steroidogenesis. Function This isoform of 17β-HSD is expressed predominantly in the testis and catalyz ...

(17β-HSD III), presents as atypical genitalia in affected males.

Signs and symptoms

17-β-Hydroxysteroid dehydrogenase III deficiency is a cause of 46,XY disorder of sex development (46,XY DSD) that presents in males with variable effects on

genitalia A sex organ, also known as a reproductive organ, is a part of an organism that is involved in sexual reproduction. Sex organs constitute the primary sex characteristics of an organism. Sex organs are responsible for producing and transporting ...

which can be complete or predominantly female with a blind vaginal pouch.

Testes A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The ...

are often found in the

inguinal canal The inguinal canal is a passage in the anterior abdominal wall on each side of the body (one on each side of the midline), which in males, convey the spermatic cords and in females, the round ligament of the uterus. The inguinal canals are lar ...

or in a bifid scrotum. Wolffian derivatives including the

epididymides The epididymis (; : epididymides or ) is an elongated tubular genital organ attached to the posterior side of each one of the two male reproductive glands, the testicles. It is a single, narrow, tightly coiled tube in adult humans, in length; ...

vas deferens The vas deferens (: vasa deferentia), ductus deferens (: ductūs deferentes), or sperm duct is part of the male reproductive system of many vertebrates. In mammals, spermatozoa are produced in the seminiferous tubules and flow into the epididyma ...

seminal vesicles The seminal vesicles (also called vesicular glands or seminal glands) are a pair of convoluted tubular accessory glands that lie behind the urinary bladder of male mammals. They secrete fluid that largely composes the semen. The vesicles are 5 ...

, and

ejaculatory duct The ejaculatory ducts (''ductus ejaculatorii'') are paired structures in the male reproductive system. Each ejaculatory duct is formed by the union of the vas deferens with the Excretory duct of seminal gland, duct of the seminal vesicle. They pa ...

s are present. The autosomal recessive deficiency arises are a result of homozygous or compound heterozygous mutations in

HSD17B3 17β-Hydroxysteroid dehydrogenase 3 (17β-HSD3) is an enzyme that in humans is encoded by the ''HSD17B3'' gene and is involved in androgen steroidogenesis. Function This isoform of 17β-HSD is expressed predominantly in the testis and catalyz ...

gene which encodes the

enzyme, impairing of the conversion of 17-keto into 17-hydroxysteroids. The enzyme is involved in the last phase of

steroidogenesis A steroid is an organic compound with four fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter memb ...

and is responsible for the conversion of

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroe ...

and

estrone Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...

estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

Virilization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is a medical term commonly used in three medical a ...

of affected males still occurs at puberty.

Genetics

17β-Hydroxysteroid dehydrogenase III deficiency is caused by

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s found in the 17β-HSD III ( 17BHSD3) gene.17β-HSD III deficiency is an autosomal recessive disorder.

Mechanism

Androstenedione is produced in the testis, as well as the

adrenal cortex The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. I ...

. Androstenedione is created from

dehydroepiandrosterone Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It funct ...

(DHEA) or 17-hydroxyprogesterone. A deficiency in the HSD17B3 gene is characterized biochemically by decreased levels of

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

to testosterone.

Diagnosis

In terms of the diagnosis of 17β-hydroxysteroid dehydrogenase III deficiency the following should be taken into account: * Increased androstenedione:testosterone ratio *

Thyroid dyshormonogenesis Thyroid dyshormonogenesis is a rare condition due to genetic defects in the synthesis of thyroid hormones. It is due to either deficiency of thyroid enzymes, inability to concentrate, or ineffective binding. Signs and symptoms The symtptoms of t ...

Genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

Management

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. A 2010 review put the risk of germ cell tumors at 17%. The management of 17β-hydroxysteroid dehydrogenase III deficiency can consist, according to one source, of the elimination of

gonads A gonad, sex gland, or reproductive gland is a mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, ...

prior to

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...

, in turn halting

masculinization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is a medical term commonly used in three medical a ...

. 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." 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.

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.Report of the UN Special Rapporteur on Torture
,

Office of the UN High Commissioner for Human Rights The Office of the United Nations High Commissioner for Human Rights (OHCHR) is a department of the United Nations Secretariat that works to promote and protect human rights that are guaranteed under international law and stipulated in the Univers ...

, February 2013.

The case of Carla

A 2016 case before the

Family Court of Australia The Family Court of Australia was a superior Australian federal court of record which deals with family law matters, such as divorce applications, parenting disputes, and the division of property when a couple separate. Together with the Fed ...

. was widely reported in national, and international media. 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 Intersex medical interventions (IMI), sometimes known as intersex genital mutilations (IGM), are surgery, surgical, hormonal and other medical interventions performed to modify atypical or ambiguous genitalia and other sex characteristics, primar ...

including a

clitorectomy Clitoridectomy or clitorectomy is the surgical removal, reduction, or partial removal of the clitoris. It is rarely used as a therapeutic medical procedure, such as when cancer has developed in or spread to the clitoris. Commonly, non-medical remo ...

and

labiaplasty Labiaplasty (also known as labioplasty, labia minora reduction, and labial reduction) is a plastic surgery procedure for creating or altering the labia minora (inner labia) and the labia majora (outer labia), the folds of skin of the human vu ...

, without requiring Court oversight, which were described by the judge as surgeries that "enhanced the appearance of her female genitalia".

Organisation Intersex International Australia Intersex Human Rights Australia (IHRA) is a voluntary organisation for intersex people that promotes the human rights and bodily autonomy of intersex people in Australia, and provides education and information services. Established in 2009 and i ...

found this "disturbing", and stated that the case was reliant on

gender stereotyping A gender role, or sex role, is a social norm deemed appropriate or desirable for individuals based on their gender or sex. Gender roles are usually centered on conceptions of masculinity and femininity. The specifics regarding these gendered ...

and failed to take account of data on cancer risks.

References

External links

{{Gonadal disorder Autosomal recessive disorders Cholesterol and steroid metabolism disorders Endocrine gonad disorders Intersex variations