17β-Hydroxysteroid dehydrogenase III deficiency

17β-Hydroxysteroid dehydrogenase III 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.
Classification and external resources
ICD-10	E29.1
OMIM	264300
DiseasesDB	32638
Orphanet	752

17β-Hydroxysteroid dehydrogenase III deficiency is a rare disorder of sexual development, or intersex condition, affecting testosterone biosynthesis by 17β-hydroxysteroid dehydrogenase III (17β-HSD III),^[1][2] which can produce impaired virilization (historically termed male pseudohermaphroditism) of genetically male infants and children and excessive virilization of female adults. It is an autosomal recessive condition and is one of the few disorders of sexual development that can affect the primary and/or secondary sex characteristics of both males and females.

Signs and symptoms

17-β-Hydroxysteroid dehydrogenase III deficiency is clinically characterized by either ambiguous external genitalia or complete female external genitalia at birth; as a consequence of impaired male sexual differentiation in 46,XY individuals, as well as:^[3][1][4]

• Hypothyroidism
• Cryptorchidism
• Infertility
• Abnormality of metabolism

Genetics

Genetically speaking, 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.^[5][6]

Biochemistry mechanism

Androstenedione

A deficiency in the HSD17B3 gene is characterized biochemically by decreased levels of testosterone and increased levels of androstenedione as a result of the defect in conversion of androstenedione into testosterone, this leads to clinically important higher ratio of androstenedione to testosterone^[7][5][8]

Androstenedione is produced in the testis, as well as the adrenal cortex. Androstenedione is created from dehydroepiandrosterone (or 17-hydroxyprogesterone).^[9]

Diagnosis

In terms of the diagnosis of 17β-hydroxysteroid dehydrogenase III deficiency the following should be taken into account:^[10][2]

• Delta(4)-A to T ratio (unusually increased)
• Thyroid dyshormonogenesis
• Genetic testing

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.^[11] A 2010 review put the risk of germ cell tumors at 17%.^[12]

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.^[2]

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."^[13] 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.^[14]

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".^[15][16][17]

Re: Carla (Medical procedure)

A 2016 case before the Family Court of Australia^[18] was widely reported in national,^[19][20][21] and international media.^[22] The judge ruled that parents were able to authorize the sterilization of their 5-year old child. 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 having "enhanced the appearance of her female genitalia".^[18] 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.^[23]

See also

• Inborn errors of steroid metabolism
• Disorders of sexual development
• Intersex
• 17β-Hydroxysteroid dehydrogenase (III)
• Sex hormone (androgen/estrogen)

References

Further reading

• Bissonnette, Bruno (2006). Syndromes: Rapid Recognition and Perioperative Implications. McGraw Hill Professional. ISBN 9780071354554. Retrieved 11 March 2017.