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 effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...

disorder of sexual development Disorders of sex development (DSDs), also known as differences in sex development, diverse sex development and variations in sex characteristics (VSC), are congenital conditions affecting the reproductive system, in which development of chromos ...

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

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...

biosynthesis by 17β-hydroxysteroid dehydrogenase III (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 (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, ...

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

Testes A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...

are often found in the

inguinal canal The inguinal canals are the two passages in the anterior abdominal wall of humans and animals which in males convey the spermatic cords and in females the round ligament of the uterus. The inguinal canals are larger and more prominent in males. ...

or in a

bifid scrotum Bifid refers to something that is split or cleft into two parts. It may refer to: * Bifid, a variation in the P wave (electrocardiography), P wave, QRS complex, R wave, or T wave in an echocardiogram in which a wave which usually has a single pea ...

. Wolffian derivatives including the

epididymides The epididymis (; plural: epididymides or ) is a tube that connects a testicle to a vas deferens in the male reproductive system. It is a single, narrow, tightly-coiled tube in adult humans, in length. It serves as an interconnection between the ...

vas deferens The vas deferens or ductus deferens is part of the male reproductive system of many vertebrates. The ducts transport sperm from the epididymis to the ejaculatory ducts in anticipation of ejaculation. The vas deferens is a partially coiled t ...

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

, and

ejaculatory duct The ejaculatory ducts (''ductus ejaculatorii'') are paired structures in male anatomy. Each ejaculatory duct is formed by the union of the vas deferens with the duct of the seminal vesicle. They pass through the prostate, and open into the ureth ...

s are present. 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 A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...

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 dehy ...

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 spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...

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 most commonly used in three medical and biology ...

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, m ...

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

Biochemistry

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 an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It ...

. 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 functio ...

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

and increased levels of androstenedione as a result of the defect in conversion of androstenedione into testosterone. 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 Patients develop h ...

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 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, produces ...

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 girl, the testes in a b ...

, in turn halting masculinization. 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, commonly known as the Office of the High Commissioner for Human Rights (OHCHR) or the United Nations Human Rights Office, is a department of the Secretariat of the United Nati ...

, 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 F ...

. 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, also known as intersex genital mutilations (IGM), are surgical, hormonal and other medical interventions performed to modify atypical or ambiguous genitalia and other sex characteristics, primarily for the purposes ...

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".

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 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