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Open access

Birgit Köhler, Lin Lin, Inas Mazen, Cigdem Cetindag, Heike Biebermann, Ilker Akkurt, Rainer Rossi, Olaf Hiort, Annette Grüters, and John C Achermann


Hypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias.

Design and methods

Mutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network.


Heterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients.


SF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common.

Free access

Sally Tantawy, Inas Mazen, Hala Soliman, Ghada Anwar, Abeer Atef, Mona El-Gammal, Ahmed El-Kotoury, Mona Mekkawy, Ahmad Torky, Agnes Rudolf, Pamela Schrumpf, Annette Grüters, Heiko Krude, Marie-Charlotte Dumargne, Rebekka Astudillo, Anu Bashamboo, Heike Biebermann, and Birgit Köhler


Steroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator of genes involved in the hypothalamic–pituitary–gonadal axis. Recently, SF1 mutations were found to be a frequent cause of 46,XY disorders of sex development (DSD) in humans. We investigate the frequency of NR5A1 mutations in an Egyptian cohort of XY DSD.


Clinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian XY DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum.


Molecular analysis of NR5A1 gene by direct sequencing followed by in vitro functional analysis of the two novel missense mutations detected.


Three novel heterozygous mutations of the coding region in patients with hypospadias were detected. p.Glu121AlafsX25 results in severely truncated protein, p.Arg62Cys lies in DNA-binding zinc finger, whereas p.Ala154Thr lies in the hinge region of SF1 protein. Transactivation assays using reporter constructs carrying promoters of anti-Müllerian hormone (AMH), CYP11A1 and TESCO core enhancer of Sox9 showed that p.Ala154Thr and p.Arg62Cys mutations result in aberrant biological activity of NR5A1. A total of 17 patients (34%) harboured the p.Gly146Ala polymorphism.


We identified two novel NR5A1 mutations showing impaired function in 23 Egyptian XY DSD patients with hypospadias (8.5%). This is the first study searching for NR5A1 mutations in oriental patients from the Middle East and Arab region with XY DSD and no adrenal insufficiency, revealing a frequency similar to that in European patients (6.5–15%). We recommend screening of NR5A1 in patients with hypospadias and gonadal dysgenesis. Yearly follow-ups of gonadal function and early cryoconservation of sperms should be performed in XY DSD patients with NR5A1 mutations given the risk of future fertility problems due to early gonadal failure.

Restricted access

Angela K Lucas-Herald, Jillian Bryce, Andreas Kyriakou, Marie Lindhardt Ljubicic, Wiebke Arlt, Laura Audí, Antonio Balsamo, Federico Baronio, Silvano Bertelloni, Markus Bettendorf, Antonia Brooke, Hedi L Claahsen-van der Grinten, Justin Davies, Gloria Hermann, Liat de Vries, Ieuan A Hughes, Rieko Tadokoro-Cuccaro, Feyza Darendeliler, Sukran Poyrazoglu, Mona Ellaithi, Olcay Evliyaoglu, Simona Fica, Lavinia Stejereanu, Aneta Gawlik, Evgenia Globa, Nataliya Zelinska, Tulay Guran, Ayla Güven, Sabine Hannema, Olaf Hiort, P-m Holterhus, Violeta Iotova, Vilhelm Mladenov, Vandana Jain, Rajni Sharma, Farida Jennane, Colin Johnston, Gil Guerra-Junior, Daniel Konrad, Odile Gaisl, Nils P Krone, Ruth Krone, Katherine Lachlan, Dejun Li, Corina Lichiardopol, Lidka Lisá, Renata Levoni Markosyan, Inas Mazen, Klaus Mohnike, Marek Niedziela, Anna Nordenstrom, Rodolfo A Rey, Mars Skae, Lloyd JW Tack, Jeremy W Tomlinson, Naomi Weintrob, Martine Cools, and S Faisal Ahmed

Objectives: To determine trends in clinical practice for individuals with DSD requiring gonadectomy.

Design: Retrospective cohort study.

Methods: Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist center; and location of center from cases reported to the International DSD Registry and who were over 16 years old in January 2019.

Results: Data regarding gonadectomy were available in 668 (88%) individuals from 44 centers. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centers in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n=311, p<0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centers, 17 (5%) at 9 centers had undergone gonadectomy before their first presentation to the specialist center. Median age at gonadectomy of cases from high income countries and low/middle income countries (LMIC) was 13.0 yrs (0.1, 68) years and 16.5 yrs (1, 28), respectively (p<0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries.

Conclusions: The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.