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Bilbao JR, L Loridan, L Audi, E Gonzalo and L Castano

OBJECTIVE: Deficit of the testosterone converting enzyme 17-beta-hydroxysteroid dehydrogenase (17beta-HSD) has been shown to be responsible for male pseudohermaphroditism (MPH). We analysed the gene encoding 17beta-HSD type 3 (17beta-HSD3) in a patient with MPH. METHODS: We studied a 46, XY new-born diagnosed as having MPH. The child also had other congenital disorders, including a giant omphalocele and Fallot's tetralogy, and died of post-surgical complications at age 4.5 months. Basal hormonal levels, and after human chorionic gonadotrophin stimulation, suggested a deficiency in 17beta-HSD as the biochemical defect underlying this MPH. PCR amplification and subsequent sequencing of all coding exons of the 17beta-HSD3 gene were performed on genomic DNA from the patient and both parents. Messenger RNA was extracted from the patient's testis and 17beta-HSD3 cDNA was synthesized, PCR amplified and sequenced. RESULTS: Sequencing revealed the presence of a homozygous missense mutation (R80W) in exon 3 of the 17beta-HSD3 gene, which was also present in single doses in both parents, in accordance with the recessive inheritance of the defect. No other mutation was found, and cDNA sequencing confirmed correct synthesis and processing of 17beta-HSD3 mRNA. CONCLUSIONS: Confirming the abnormal delta4-androstenedione/testosterone ratios that suggested 17beta-HSD deficiency, a homozygous missense mutation in the gene coding for this enzyme was identified in the patient with MPH. This study adds further genetic evidence to the role of 17beta-HSD3 in male sexual development. There is no evidence supporting the association of this mutation in 17beta-HSD3 with the congenital malformations other than MPH present in the child.

Restricted access

M. Millán, L. Audí, J. Martinez-Mora, M.J. Martinez de Osaba, J. Viguera, E. Esmatjes, M. Peig and E. Vilardell


A 24 years old male with pseudohermaphroditism due to a deficiency in 17-ketosteroid reductase activity is described. Plasma Δ4 is 21 times higher than normal for an adult male, Δ4/T is greater than 6, both E1 and E2 are elevated and E1/E2 = 3.

There is very slight modification of Δ4 on administration of ACTH, dexamethasone, hCG and fluoxymesterone. Steroid concentrations in the spermatic veins and arteries confirm the testicular origin of the increased secretion of Δ4 and E1 and show a lower secretion by the cryptorchidic testis.

In vitro testicular tissue incubation and fibroblast studies confirm the 17-ketosteroid reductase deficiency and rule out any other anomaly as the cause of the ambiguous genitalia.

Psychologically the patient seemed to be identified with a female social and sexual role in spite of her advanced degree of virilization.

Open access

L Audí, S F Ahmed, N Krone, M Cools, K McElreavey, P M Holterhus, A Greenfield, A Bashamboo, O Hiort, S A Wudy, R McGowan and the EU COST Action

The differential diagnosis of differences or disorders of sex development (DSD) belongs to the most complex fields in medicine. It requires a multidisciplinary team conducting a synoptic and complementary approach consisting of thorough clinical, hormonal and genetic workups. This position paper of EU COST (European Cooperation in Science and Technology) Action BM1303 ‘DSDnet’ was written by leading experts in the field and focuses on current best practice in genetic diagnosis in DSD patients. Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step. Subsequently, further analyses comprise molecular studies of monogenic DSD causes or analysis of copy number variations (CNV) or both. Panels of candidate genes provide rapid and reliable results. Whole exome and genome sequencing (WES and WGS) represent valuable methodological developments that are currently in the transition from basic science to clinical routine service in the field of DSD. However, in addition to covering known DSD candidate genes, WES and WGS help to identify novel genetic causes for DSD. Diagnostic interpretation must be performed with utmost caution and needs careful scientific validation in each DSD case.