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

Orpha number ORPHA752
Synonym(s) 17-beta-hydroxysteroid dehydrogenase 3 deficiency
17-ketoreductase deficiency
17-ketosteroidreductase deficiency
Male pseudohermaphroditism due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency
Prevalence 1-9 / 1 000 000
Inheritance
  • Autosomal recessive
Age of onset Neonatal/infancy
ICD-10
  • E29.1
OMIM
UMLS
  • C0268296
MeSH -
MedDRA -
SNOMED CT
  • 50658006

Summary

17-beta-hydroxysteroid dehydrogenase isozyme 3 (17betaHSD III) deficiency is a rare disorder leading to male pseudohermaphroditism (MPH), a condition characterized by incomplete differentiation of the male genitalia in 46X,Y males. The estimated incidence of this disease is 1 in 147 000 in The Netherlands. The 17betaHSD III enzyme catalyzes the conversion of androstenedione to testosterone in the testis. Lack of testosterone in the fetal testis leads to genetic males with female external genitalia. Patients usually present at birth with female or ambiguous external genitalia, characterized by clitoromegaly, posterior labioscrotal fusion and perineal blind vaginal pouch. Testes are inguinal or in the labioscrotal folds. The internal urogenital tract (epididymides, vasa deferentia, seminal vesicles, ejaculatory ducts) is well developed; prostate and Müllerian structures are absent. Although some patients with less severe defects are brought up as males, affected males are usually brought up as females. However, at puberty they develop signs of virilization (phallic enlargement, male secondary sexual characteristics) and gynecomastia as the result of increases in serum testosterone, due to the conversion of androstenedione to testosterone by extra-gonadal 17b-HSD isoenzymes. All affected individuals are infertile. The disorder is transmitted as an autosomal recessive trait. At least 20 mutations have been reported in the 17-beta-HSD type 3 isozyme gene (HSD17B3), localized to 9q22. These are mainly missense/nonsense mutations, without significant genotypic/phenotypic correlation. Baseline and post-hCG (human chorionic gonadotropin) stimulation hormonal evaluation demonstrates increased androstenedione and low testosterone levels, with an elevated androstenedione/testosterone ratio. Before puberty, a hCG stimulation test is often necessary for diagnosis, since basal levels may be uninformative. Deficiency of 17-ketosteroid reductase is often misdiagnosed in infancy and detected at puberty in genetic males who have been either raised as females and develop hirsutism and primary amenorrhoea, or raised as males and have gynecomastia and incomplete male genital development. If the diagnosis is made at birth, gender assignment must be discussed, depending on the expected results of masculinizing genitoplasty. If female assignment is selected, feminizing genitoplasty and gonadectomy must be performed. Prenatal diagnosis is available for the kindred of affected patients if causal mutations have been characterized.

Expert reviewer(s)

  • Dr Caroline SEVIN

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